Bicyclic Pyrrole Derivatives

ABSTRACT

Compounds represented by the general formula (I), prodrugs thereof, or pharmaceutically acceptable salts of both are provided as compounds which have high DPP-IV inhibiting activity and are improved in safety, toxicity and so on: (I) 
     
       
         
         
             
             
         
       
     
     wherein the solid line and dotted line between A 1  and A 2  represents a double bond (A 1 =A 2 ) or the like; A 1  is C(R 4 ) or the like; A 2  is nitrogen atom or the like; R 1  is hydrogen atom, optionally substituted alkyl group, or the like; R 2  is hydrogen atom, optionally substituted alkyl group, or the like; R 3  is hydrogen atom, halogen atom, or the like; R 4  is hydrogen atom, hydroxyl, halogen atom, or the like; and Y is a group represented by the general formula (A) or the like; (A) 
     
       
         
         
             
             
         
       
     
     [wherein m1 is 0, 1, 2 or 3; and the group (A) may be freed from R 6  or substituted with one or two R 6 &#39;s which are each independently halogen atom or the like.]

TECHNICAL FIELD

The present invention relates to bicyclic pyrrole derivatives useful as drugs. More particularly, it relates to novel bicyclic pyrrole derivatives effective as a dipeptidyl peptidase IV (DPP-IV) inhibitor. Furthermore, it relates to a pharmaceutical composition for the treatment of diabetes containing a bicyclic pyrrole derivative effective as a dipeptidyl peptidase IV (DPP-IV) inhibitor, as an active ingredient.

BACKGROUND ART

DPP-IV is a serine protease widely present in the body, is one of dipeptidyl aminopeptidases capable of hydrolyzing and releasing a N-terminal dipeptide and markedly acts on, in particular, peptides containing proline as the second amino acid from the N-terminal. Therefore, DPP-IV is referred to also as prolyl end peptidase. DPP-IV is known to accept, as substrates, various biological peptides concerned in the endocrine system, the neuroendocrine system, immunological functions and the like. It is known that many physiologically active peptides such as the pancreatic polypeptide family represented by pancreatic polypeptides (PP), neuropeptide Y (NPY) and the like; the glucagon/VIP family represented by vasoactive intestinal polypeptides (VIP), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptides (GIP), growth hormone-releasing factor (GRF) and the like; and the chemocaine family are substrates for DPP-IV and are subject to the influences of DPP-IV, such as activation/inactivation, metabolism acceleration and the like (non-patent document 1).

DPP-IV severs two amino acids (His-Ala) from the N-terminal of GLP-1. It is known that although the severed peptide binds weekly to a GLP-1 receptor, it has no activating effect on the receptor and acts as an antagonist (non-patent document 2). The metabolism of GLP-1 by DPP-IV in blood is known to be very rapid, and the concentration of active GLP-1 in blood is increased by the inhibition of DPP-IV (non-patent document 3). GLP-1 is a peptide secreted from intestinal tract by the ingestion of sugars and is a main accelerating factor for the glucose-responsive secretion of insulin by pancreas. In addition, GLP-1 is known to have accelerating effect on insulin synthesis in pancreatic β cells and accelerating effect on β cell proliferation. Moreover, it is known that GLP-1 receptors appear also in digestive tracts, liver, muscle, adipose tissue and the like, and it is also known that in these tissues, GLP-1 affects working of the digestive tracts, the secretion of acid in stomach, the synthesis and degradation of glycogen, insulin-dependent glucose uptake, and the like. Accordingly, there is expected the development of a DPP-IV inhibitor effective against type 2 diabetes (non-insulin-dependent diabetes) which brings about effects such as the acceleration of insulin secretion dependent on blood sugar level, the improvement of pancreas function, the improvement of a high postprandial blood sugar level, the improvement of glucose tolerance abnormality, the improvement of insulin resistance, and the like, by increasing the concentration of GLP-1 in blood (non-patent document 4).

Various DPP-IV inhibitors have been reported. For example, patent documents 1 and 2 report that derivatives having an imidazole ring are effective as DPP-IV inhibitors.

-   Patent document 1: International Publication No. WO02/068420     pamphlet -   Patent document 2: International Publication No. WO03/104229     pamphlet -   Non-patent document 1: J. Langner and S. Ansorge, “Cellular     Peptidases in Immune Functions and Disease 2”, Advances in     Experimental Medicine and Biology Vol. 477 -   Non-patent document 2: L. B. Knudsen et al., European Journal of     Pharmacology, Vol. 318, p 429-435, 1996 -   Non-patent document 3: T. J. Kieffer et al., Endocrinology, Vol.     136, p 3585-3596, 1995 -   Non-patent document 4: R. A. Pederson et al., Diabetes Vol. 47, p     1253-1258, 1998

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide a novel compound having an excellent DPP-IV inhibiting activity.

Means for Solving the Problem

The present inventors earnestly investigated in order to achieve the above object, and consequently found that the following compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug (if necessary, they are hereinafter abbreviated as the present inventive compounds in some cases) has an excellent DPP-IV inhibiting effect, whereby the present invention has been accomplished.

That is, the present invention relates to the following:

[1] A compound represented by the formula (I):

wherein R¹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;

the solid line and dotted line between A¹ and A² indicate a double bond (A¹=A²) or a single bond (A¹-A²);

A¹ is a group represented by the formula C(R⁴) and A² is a nitrogen atom, in the case of the solid line and dotted line between A¹ and A² being a double bond (A¹=A²);

A¹ is a group represented by the formula C═O and A² is a group represented by the formula N(R⁵), in the case of the solid line and dotted line between A¹ and A² being a single bond (A¹-A²);

R² is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group;

R³ is a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkoxy group, or the formula: -Rd-C(O)O—Re wherein Rd is a single bond, an alkylene group or an alkenylene group and Re is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-(tert-butyl)-2-oxo-1,3-dioxolen-4-ylmethyl or the formula: —CH(R^(4a))OC(O)R^(4b) wherein R^(4a) is a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group or an alkoxy group and R^(4b) is an optionally substituted alkyl group, an optionally substituted alkenyl group, a cycloalkyl group, a cycloalkyloxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, a 2-indanyloxy group, a 5-indanyloxy group or an optionally substituted aryloxy group;

R⁴ is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined above;

R⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted vinyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, or an optionally substituted heteroaryl group;

—Y is a group represented by any of the formula (A), formula (B), formula (C) and formula (D) shown below:

wherein m1 is 0, 1, 2 or 3, and R⁶ is absent or one or two R⁶s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁶s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;

wherein m2 is 0, 1, 2 or 3, and R⁷ is absent or one or two R⁷s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁷s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;

wherein m3 and m4 are independently 0 or 1, and R⁸ is absent or one or two R⁸s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁸s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; and

wherein m5 is 1, 2 or 3, R⁹ is absent or one or two R⁹s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁹s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring, and R¹⁰ and R¹¹ are independently a hydrogen atom, methyl, ethyl, propyl or isopropyl, or R¹⁰ and R¹¹, when taken together, represent cyclopropyl, cyclobutyl or cyclopentyl, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug. [2] A compound according to [1], which is represented by the formula (II):

wherein R¹, R², R³ and Y are as defined in [1] and R¹² is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. [3] A compound according to [1], which is represented by the formula (III):

wherein R¹, R², R³ and Y are as defined in [1] and R¹³ is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in [1], a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. [4] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [3], wherein R¹³ is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, a trifluoromethyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aroyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in [1]. [5] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [4], wherein R² is a group represented by any of the following formula (E), formula (F), formula (G), formula (H), formula (I) and formula (J):

wherein each of Z¹ and Z² is an oxygen atom, the formula S(O)_(p) or the formula N(R²²);

each of R¹⁴ and R²⁰ is absent or one or two R¹⁴s and/or one or two R²⁰s are present and are independently a halogen atom, a hydroxyl group, a formyl group, a carboxyl group, a cyano group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a cycloalkylcarbonyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing heteroaryl group, or two R¹⁴s or two R²⁰s, when taken together, represent a C₁₋₃ alkylenedioxy group;

each of R¹⁵ and R²¹ is absent or one or two R¹⁵s and/or one or two R²¹s are present and are independently a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group or a haloalkoxy group;

R¹⁶ is methyl, ethyl, a chlorine atom or a bromine atom;

R¹⁷ is a hydrogen atom, methyl, ethyl, a chlorine atom or a bromine atom;

R¹⁸ is a hydrogen atom, methyl or ethyl;

R¹⁹ is a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl;

p is 0, 1 or 2; and

R²² is a hydrogen atom or an alkyl group.

[6] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [5], wherein —Y is a group represented by the formula (A) in which m1 is 1 or 2, or —Y is a group represented by the formula (B) in which m2 is 1 or 2, or —Y is a group represented by the formula (C) in which each of m3 and m4 is 1. [7] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [6], wherein R² is a group represented by any of the formula (E), formula (H) and formula (I). [8] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [7], wherein R¹ is a hydrogen atom, an optionally substituted C₁-C₃ alkyl group or an optionally substituted aryl group, and the substituent(s) of the optionally substituted alkyl group is selected from fluorine atom, optionally substituted aroyl groups, carboxyl group, optionally substituted alkoxycarbonyl groups, optionally substituted aryl groups and optionally substituted aryloxy groups. [9] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [7], wherein R¹ is a group represented by the formula: —Ra—Rb—Rc in which

Ra is an alkylene group;

Rb is a single bond or a carbonyl group; and

Rc is an optionally substituted alkyl group,

an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group or an optionally substituted heteroarylamino group. [10] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [7], wherein R¹ is a hydrogen atom, methyl or ethyl. [11] A compound according to [1], which is represented by the formula (IV):

wherein R¹ and R³ are as defined in [1]; R²³ is a hydrogen atom or an optionally substituted alkyl group; R²⁴ is a halogen atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group; and R²⁵ is a hydrogen atom, a fluorine atom or a chlorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. [12] A compound according to [1], which is represented by the formula (V):

wherein R²⁶ is a hydrogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted carbamoyl group, a hydroxyl group or an optionally substituted alkoxy group; R²⁷ is a chlorine atom, a bromine atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group; and R²⁸ is a hydrogen atom or a fluorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. [13] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [12], wherein R²⁷ is a chlorine atom or a cyano group. [14] A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to either [12] or [13], wherein R²⁶ is a hydrogen atom or an optionally substituted carbamoyl group. [15] A compound represented by the formula (VI):

wherein R² and Y are as defined in [1] and R²⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. [16] A pharmaceutical composition comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] as an active ingredient. [17] A dipeptidyl peptidase IV inhibitor comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] as an active ingredient. [18] A pharmaceutical composition for the treatment of diabetes comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] as an active ingredient. [19] Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] in the manufacture of a dipeptidyl peptidase IV inhibitor. [20] Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] in the manufacture of a pharmaceutical composition for the treatment of diabetes. [21] A method for treating diabetes comprising administering an effective amount of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] to a patient who needs the treatment.

The compound represented by the formula (I), a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug is hereinafter generically named “the present inventive compound” if necessary.

ADVANTAGES OF THE INVENTION

The present inventive compound has an excellent DPP-IV inhibiting activity and is useful as a therapeutic agent for diabetes.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in further detail.

In the present description, the number of substituents of each group defined by the term “optionally substituted” or “substituted” is not particularly limited as long as the substitution is possible, and it is 1 or more. Unless otherwise specified, the explanation of each group applies also to the case where the group is a portion or the substituent of another group.

The “halogen atom” includes, for example, fluorine atom, chlorine atom, bromine atom and iodine atom.

The “alkyl group” includes, for example, linear or branched alkyl groups of 1 to 6 carbon atoms. Specific examples thereof are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. Preferable examples thereof are linear or branched alkyl groups of 1 to 4 carbon atoms. Specific examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.

The “alkenyl group” includes, for example, alkenyl groups of 2 to 6 carbon atoms. Specific examples thereof are vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl, etc.

The “alkynyl group” includes, for example, alkynyl groups of 2 to 6 carbon atoms. Specific examples thereof are ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl, etc.

The “cycloalkyl group” includes, for example, cycloalkyl groups of 3 to 10 carbon atoms. Specific examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, etc. Preferable examples thereof are cycloalkyl groups of 3 to 6 carbon atoms. Specific examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The “alkylene group” includes, for example, alkylene groups of 1 to 3 carbon atoms. Specific examples thereof are methylene, ethylene, trimethylene, etc.

The “alkenylene group” includes, for example, alkenylene groups of 2 to 4 carbon atoms. Specific examples thereof are vinylene, propenylene, butenylene, etc.

The “aryl group” includes, for example, aryl groups of 6 to 10 carbon atoms. Specific examples thereof are phenyl, 1-naphthyl, 2-naphthyl, etc.

The “aralkyl group” includes, for example, groups formed by bonding of an aryl group to an alkylene group. Specific examples thereof are benzyl, 2-phenylethyl, 1-naphthylmethyl, etc.

The “heteroaryl group” includes, for example, 5- to 10-membered monocyclic or polycyclic groups containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples thereof are pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo[1,2-a]pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl, isoquinolinolyl, etc. Preferable examples thereof are 5- or 6-membered groups containing a heteroatom selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples of such groups are pyridyl, thienyl, furyl, etc.

The heteroaryl portion of the “heteroarylalkyl group” includes the groups exemplified above as the heteroaryl group.

The “alkylcarbonyl group” includes, for example, alkylcarbonyl groups of 2 to 4 carbon atoms. Specific examples thereof are acetyl, propionyl, butyryl, etc.

The “cycloalkylcarbonyl group” includes cycloalkylcarbonyl groups of 4 to 11 carbon atoms, and the like. Specific examples thereof are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, norbornylcarbonyl, etc. Preferable examples thereof are cycloalkylcarbonyl groups of 4 to 7 carbon atoms. Specific examples of such groups are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.

The “aroyl group” includes, for example, aroyl groups of 7 to 11 carbon atoms. Specific examples thereof are benzoyl, 1-naphthoyl, 2-naphthoyl, etc.

The heteroaryl portion of the “heteroarylcarbonyl group” includes the groups exemplified above as the heteroaryl group.

The “alkoxycarbonyl group” includes, for example, alkoxycarbonyl groups of 2 to 5 carbon atoms. Specific examples thereof are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, etc.

The “aryloxycarbonyl group” includes aryloxycarbonyl groups of 7 to 11 carbon atoms, and the like. Specific examples thereof are phenyloxycarbonyl, 2-naphthyloxycarbonyl, 1-naphthyloxycarbonyl, etc.

The “alkoxy group” includes, for example, alkoxy groups of 1 to 4 carbon atoms. Specific examples thereof are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

The “cycloalkyloxy group” includes, for example, cycloalkyloxy groups of 3 to 10 carbon atoms. Specific examples thereof are cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy, norbornyloxy, etc. Preferable examples thereof are cycloalkyloxy groups of 3 to 6 carbon atoms. Specific examples of such groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

The cycloalkyloxy portion of the “cycloalkyloxycarbonyl group” includes the groups exemplified above as the cycloalkyloxy group.

The “aryloxy group” includes, for example, aryloxy groups of 6 to 10 carbon atoms. Specific examples thereof are phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc.

The aralkyl portion of the “aralkyloxy group” includes the groups exemplified above as the aralkyl group. Specific examples thereof are benzyloxy, 2-phenylethyloxy, etc.

The aralkyl portion of the “aralkyloxycarbonyl group” includes the groups exemplified above as the aralkyl group.

The heteroaryl portion of the “heteroaryloxy group” includes the groups exemplified above as the heteroaryl group.

The “alkylthio group” includes, for example, alkylthio groups of 1 to 6 carbon atoms. Specific examples thereof are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc. Preferable examples thereof are alkylthio groups of 1 to 4 carbon atoms. Specific examples of such groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.

The “alkylsulfinyl group” includes, for example, alkylsulfinyl groups of 1 to 6 carbon atoms. Specific examples thereof are methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc. Preferable examples thereof are alkylsulfinyl groups of 1 to 4 carbon atoms. Specific examples of such groups are methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.

The “alkylsulfonyl group” includes, for example, alkylsulfonyl groups of 1 to 6 carbon atoms. Specific examples thereof are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc. Preferable examples thereof are alkylsulfonyl groups of 1 to 4 carbon atoms. Specific examples of such groups are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, etc.

The “arylthio group” includes, for example, arylthio groups of 6 to 10 carbon atoms. Specific examples thereof are phenylthio, 1-naphthylthio, 2-naphthylthio, etc.

The “arylsulfinyl group” includes, for example, arylsulfinyl groups of 6 to 10 carbon atoms. Specific examples thereof are phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.

The “arylsulfonyl group” includes, for example, arylsulfonyl groups of 6 to 10 carbon atoms. Specific examples thereof are phenylsulfonyl, tosyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.

The “nitrogen-containing saturated heterocyclic group” includes, for example, 5- or 6-membered saturated heterocyclic groups which have one or two nitrogen atoms and may further have an oxygen atom or a sulfur atom. Specific examples thereof are pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, etc.

The substituent(s) of the “optionally substituted alkyl group” includes, for example, (1) halogen atoms, (2) hydroxyl group, (3) cyano group, (4) carboxyl group, (5) optionally substituted cycloalkyl groups, (6) optionally substituted aryl groups, (7) optionally substituted heteroaryl groups, (8) optionally substituted aroyl groups, (9) optionally substituted heteroarylcarbonyl groups, (10) optionally substituted arylaminocarbonyl groups, (11) optionally substituted heteroarylaminocarbonyl groups, (12) optionally substituted aryloxy groups, (13) optionally substituted arylsulfonyl groups, (14) optionally substituted aralkylsulfonyl groups, (15) optionally substituted alkoxy groups, (16) optionally substituted cycloalkyloxy groups, (17) optionally substituted alkoxycarbonyl groups, (18) optionally substituted aryloxycarbonyl groups, (19) optionally substituted amino groups, (20) optionally substituted carbamoyl groups, (21) alkylsulfonyl groups, (22) optionally substituted alkylcarbonyl groups, (23) cycloalkyloxycarbonyl groups, (24) tetrahydrofuranyloxycarbonyl group, and (25) tetrahydrofuranyl group.

The above items (1) to (25) are explained below.

The substituents of the “optionally substituted cycloalkyl groups” of the above item (5) include, for example, alkyl groups, aralkyl groups, alkoxy groups, alkoxycarbonyl groups and fluorine atom.

The substituents of the “optionally substituted aryl groups” of the above item (6) include those exemplified hereinafter as the substituent(s) of the “optionally substituted aryl group”.

The substituents of the “optionally substituted heteroaryl groups” of the above item (7) include, for example,

(a) hydroxyl group, (b) halogen atoms, (c) alkyl groups, (d) alkyl groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy), (e) alkoxy groups, (f) alkoxy groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy), (g) cyano group, (h) carboxyl group, (i) alkoxycarbonyl groups, (j) carbamoyl groups which may be substituted by an alkyl group(s) (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl), (k) aryl groups, and (1) amino group.

The substituents of the “optionally substituted aroyl groups” of the above item (8) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).

The substituents of the “optionally substituted heteroarylcarbonyl groups” of the above item (9) include those exemplified as the substituents of the “optionally substituted heteroaryl groups” of the above item (7).

The substituents of the “optionally substituted arylaminocarbonyl groups” of the above item (10) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).

The substituents of the “optionally substituted heteroarylaminocarbonyl groups” of the above item (11) include those exemplified as the substituents of the “optionally substituted heteroaryl groups” of the above item (7).

The substituents of the “optionally substituted aryloxy groups” of the above item (12) and the “optionally substituted arylsulfonyl groups” of the above item (13) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).

The aralkyl portion of the “optionally substituted aralkylsulfonyl group” of the above item (14) includes the groups exemplified above as the aralkyl group.

The substituents of the “optionally substituted aralkylsulfonyl groups” include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).

The substituents of the “optionally substituted alkoxy groups” of the above item (15) include, for example,

(a) hydroxyl group, (b) carboxyl group, (c) alkoxy groups, (d) alkoxycarbonyl groups, (e) amino groups which may be substituted by an alkyl group(s) (for example, amino, dimethylamino and diethylamino), (f) carbamoyl groups substituted by an alkyl group(s), (g) sulfamoyl groups substituted by an alkyl group(s), (h) ureido groups substituted by an alkyl group(s), (i) phenyl groups which may be substituted by a halogen atom or an alkoxy group (for example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-isopropoxyphenyl and 3-isopropoxyphenyl), (j) 5-oxo-2-tetrahydrofuranyl, (k) 1,3-dihydro-3-oxo-1-isobenzofuranyl, (l) tetrahydrofuranyl, (m) nitrogen-containing saturated heterocyclic groups, (n) alkoxy groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy), (o) cycloalkyl groups, (p) cycloalkyl groups substituted by a halogen atom or an alkoxy group (for example, 2-fluorocyclopropyl, 2-methoxycyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl and 3-methoxycyclobutyl), and (q) halogen atoms.

The substituents of the “optionally substituted cycloalkyloxy groups” of the above item (16) and the “optionally substituted alkoxycarbonyl groups” of the above item (17) include those exemplified as the substituents of the “optionally substituted alkoxy groups” of the above item (15).

The substituents of the “optionally substituted aryloxycarbonyl groups” of the above item (18) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).

The substituents of the “optionally substituted amino groups” of the above item (19) include, for example,

(a) alkyl groups, (b) alkylcarbonyl groups, (c) aroyl groups, (d) alkylsulfonyl groups, (e) arylsulfonyl groups, (f) optionally substituted aryl groups (their substituents include, for example, halogen atoms, alkyl groups and alkoxy groups), (g) alkoxycarbonylmethyl groups (the carbon atom of the methyl portion may be substituted by one or two alkyl groups, and the two alkyl groups on the carbon atom of the methyl portion may bind to each other to form cyclopropyl, cyclobutyl or cyclopentyl together with the carbon atom of the methyl portion), and (h) aralkyl groups.

As the optionally substituted amino groups, (i) imides are also exemplified.

The substituents of the “optionally substituted carbamoyl groups” of the above item (20) include, for example, alkyl groups and cycloalkyl groups. The two substituents of the carbamoyl group may bind to each other to form an aliphatic heterocyclic ring which may contain carbon atoms, a nitrogen atom(s) and/or an oxygen atom(s), such as pyrrolidine (which may be substituted by a hydroxyl group), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperazine (the nitrogen atom of this piperazine may be substituted by methyl or ethyl), or the like.

Specific examples of the “optionally substituted carbamoyl groups” are carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, cyclopropylcarbamoyl, cyclopropylmethylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, etc.

The substituents of the “optionally substituted alkylcarbonyl groups” of the above item (22) include, for example,

(a) halogen atoms, (b) alkoxy groups, (c) cycloalkyl groups, (d) alkoxycarbonyl groups, (e) optionally substituted aryl groups (their substituents include, for example, halogen atoms, alkyl groups, alkoxy groups and alkoxycarbonyl groups), and (f) hydroxyl group.

The substituent(s) of each of the “optionally substituted alkylthio group”, “optionally substituted alkylsulfinyl group” and “optionally substituted alkylsulfonyl group” includes those exemplified as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

The substituent(s) of each of the “optionally substituted alkenyl group” and the “optionally substituted alkynyl group” includes, for example,

(1) hydroxyl group, (2) halogen atoms, (3) alkyl groups, (4) alkyl groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropyl), (5) alkoxy groups, (6) alkoxy groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy), (7) phenyl groups or aroyl groups, which may be substituted by the following (aa), (bb) or (cc):

(aa) an alkoxy group(s) which may be substituted by a halogen atom(s) or an alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy),

(bb) an alkyl group(s) which may be substituted by a halogen atom(s) (for example, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl and 1-(difluoromethyl)-2,2-difluoroethyl),

(cc) a halogen atom(s),

(8) cyano group, (9) carboxyl group, (10) alkoxycarbonyl groups, (11) carbamoyl groups which may be substituted by an alkyl group(s) (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl), (12) alkylsulfonyl groups, and (13) phenyloxy group.

The substituent(s) of the “optionally substituted vinyl group” includes, for example, halogen atoms and alkyl groups.

Specific examples of the substituted vinyl groups are 1-propylene, 2-methyl-1-propylene, 2-chloro-1-propylene, etc.

The substituent(s) of the “optionally substituted cycloalkyl groups” includes those exemplified as the substituents of (5) the “optionally substituted cycloalkyl groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

The substituent(s) of the “optionally substituted aryl group” includes, for example,

(1) hydroxyl group, (2) halogen atoms, (3) alkyl groups, (4) alkyl groups substituted by a halogen atom(s), an alkoxy group or a cycloalkyl group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropyl), (5) phenyl groups which may be substituted by the following (aa), (bb) or (cc):

(aa) an alkoxy group(s) which may be substituted by a halogen atom(s) or an alkoxy group (for example, methioxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy),

(bb) an alkyl group(s) which may be substituted by a halogen atom(s) (for example, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl and 1-(difluoromethyl)-2,2-difluoroethyl),

(cc) a halogen atom(s),

(6) cyano group, (7) carboxyl group, (8) alkoxycarbonyl groups which may be substituted by a halogen atom(s) (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, fluoromethoxycarbonyl, difluoromethoxycarbonyl, 2,2-difluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, methoxycarbonyl and ethoxycarbonyl), (9) carbamoyl groups which may be substituted by an alkyl group(s) (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl), (10) alkylsulfonyl groups, (11) C₁₋₃ alkylenedioxy groups, (12) formyl group, (13) optionally substituted phenyloxy groups (their substituents include, for example, halogen atoms, alkyl groups and alkoxy groups), (14) nitrogen-containing saturated heterocyclic groups (for example, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl (the nitrogen atom of the piperazine may be substituted, for example, by methyl, ethyl or propyl)), (15) cycloalkyloxy groups which may be substituted by a hydroxyl group, an oxo group, a carboxyl group, a carboxymethyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group (e.g. methoxycarbonylmethyl, ethoxycarbonylmethyl or isopropoxycarbonylmethyl), an alkyl group, a fluoroalkyl group (e.g. fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or perfluoroethyl), an alkoxyalkyl group (e.g. methoxymethyl, ethoxymethyl or isopropoxymethyl), a cycloalkyloxyalkyl group (e.g. cyclopropyloxymethyl, cyclopropyloxyethyl or cyclobutyloxy), an alkoxy group, a cycloalkyloxy group or a halogen atom(s) (for example, 3-carboxycyclobutyloxy, 3-methoxycarbonylcyclobutyloxy, 3-ethoxycarbonylbutyloxy, 2-methylcyclopropyloxy, 2-fluorocyclopropyloxy, 3-methoxycyclobutyloxy, 3-fluorocyclobutyloxy, 3,3-difluorocyclobutyloxy and 3-(2-fluoroethyl)cyclobutyloxy), (16) alkoxy groups which may be substituted by a hydroxyl group, an oxo group, a carboxyl group, an alkoxycarbonyl group, a cycloalkyl group, an alkoxy group, a cycloalkyloxy group, an optionally substituted oxygen-containing heterocyclic group (e.g. a 5- or 6-membered saturated heterocyclic group having an oxygen atom(s), specific examples of which are tetrahydrofuranyl, tetrahydropyranyl, etc.; the substituent(s) includes, for example, halogen atoms, oxo group and alkoxy groups), or a halogen atom(s) (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-hydroxyethoxy, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, cyclopropylmethoxy, cyclobutylmethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, isopropoxymethoxy, cyclopropyloxymethoxy, cyclobutoxymethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy and 1-(difluoromethyl)-2,2-difluoroethoxy), (17) difluoromethylenedioxy, (18) alkenyl groups which may be substituted by a halogen atom (for example, vinyl, propenyl, methylpropenyl, butenyl and methylbutenyl), (19) amino groups which may be substituted by an alkyl group(s) (for example, amino, methylamino, ethylamino, propylamino, dimethylamino, methylethylamino and diethylamino), (20) optionally substituted alkylcarbonyl groups

(their substituents include, for example, halogen atoms, alkoxy groups and cycloalkyl groups),

(21) alkylcarbonyloxy groups (for example, methylcarbonyloxy, ethylcarbonyloxy and isopropylcarbonyloxy), (22) cycloalkyl groups which may be substituted by a fluorine atom (for example, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutylcyclobutyl, adamantyl and norbornyl), (23) cycloalkylcarbonyl groups which may be substituted by a fluorine atom (for example, cyclopropylcarbonyl, 2-fluorocyclopropylcarbonyl, cyclobutylcarbonyl and cyclopentylcarbonyl), (24) alkylthio groups, (25) alkylsulfinyl groups, (26) optionally substituted heteroaryl groups (their substituents include, for example, halogen atoms, alkyl groups, alkoxy groups, haloalkyl groups and haloalkoxy groups), (27) groups represented by the following formulas (T1) to (T16):

wherein R^(T) is absent or one or more R^(T)s are present and are independently a halogen atom, a hydroxyl group, an oxo group, a carboxyl group, an optionally substituted alkyl group (its substituent(s) includes, for example, halogen atoms and alkoxy groups), an optionally substituted alkoxycarbonyl group (its substituent(s) includes, for example, halogen atoms and alkoxy groups), an optionally substituted alkoxy group (its substituent(s) includes, for example, halogen atoms and alkoxy groups), an optionally substituted carbamoyl group (its substituent(s) includes, for example, alkyl groups), or a saturated heterocyclic group oxycarbonyl group (the saturated heterocyclic group includes, for example, 5- or 6-membered saturated heterocyclic groups having an oxygen atom(s), a nitrogen atom(s) and/or a sulfur atom(s), each in a number of 1 or 2, specific examples of which are tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrothiopyranyl, tetrahydrodioxothiopyranyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl and thiazolidinyl), or two RTS, when taken together, may represent methylene, ethylene, trimethylene, tetramethylenel or butenylene and may bind to one or more carbon atoms constituting the ring, to form a new ring; and R^(X) is a hydrogen atom or an alkyl group, (28) aroyl groups, and (29) groups represented by the formula: -Rd-CO(O)—Re wherein Rd and Re are as defined above.

The substituent(s) of each of the “optionally substituted heteroaryl group”, “optionally substituted aralkyl group”, “optionally substituted heteroarylalkyl group”, “optionally substituted aroyl group”, “optionally substituted heteroarylcarbonyl group”, “optionally substituted aryloxycarbonyl group”, “optionally substituted aryloxy group”, “optionally substituted aralkyloxy group”, “optionally substituted aralkyloxycarbonyl group”, “optionally substituted heteroaryloxy group”, “optionally substituted arylthio group”, “optionally substituted arylsulfinyl group” and “optionally substituted arylsulfonyl group” includes those exemplified as the substituent(s) of the above-mentioned “optionally substituted aryl group”.

The substituent(s) of the “optionally substituted alkylcarbonyl group” includes those exemplified as the substituents of (22) the “optionally substituted alkylcarbonyl groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

The substituent(s) of the “optionally substituted cycloalkylcarbonyl group” includes, for example, halogen atoms and alkoxy groups.

The substituent(s) of each of the “optionally substituted alkoxy group” and the “optionally substituted alkoxycarbonyl group” includes those exemplified as the substituents of (15) the “optionally substituted alkoxy groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

The substituent(s) of each of the “optionally substituted cycloalkyloxy group” and the “optionally substituted cycloalkyloxycarbonyl group” includes those exemplified as the substituents of (16) the “optionally substituted cycloalkyloxy groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

The substituent(s) of the “optionally substituted amino group” includes those exemplified as the substituents of (19) the “optionally substituted amino groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

The substituent(s) of the “optionally substituted carbamoyl group” includes, for example,

(1) optionally substituted alkyl groups (their substituents include, for example, hydroxyl group, halogen atoms, alkoxy groups optionally substituted by a halogen atom(s), cycloalkoxy groups optionally substituted by a halogen atom(s), and tetrahydrofuranyl), (2) cycloalkyl groups which may be substituted by a halogen atom(s), (3) aryl groups which may be substituted by the following (aa), (bb), (cc) or (dd):

(aa) a halogen atom(s),

(bb) an alkoxy group(s) which may be substituted by a halogen atom(s) (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy and 1-(difluoromethyl)-2,2-difluoroethoxy),

(cc) an alkyl group(s) which may be substituted by a halogen atom(s) (for example, methyl, ethyl, propyl, isopropyl, butyl, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl and 1-(difluoromethyl)-2,2-difluoroethyl),

(dd) a C₁₋₃ alkylenedioxy group(s),

(4) alkylsulfonyl groups, (5) cycloalkylsulfonyl groups, (6) optionally substituted arylsulfonyl groups (their substituents include, for example, halogen atoms, alkyl groups, haloalkyl groups, alkoxy groups and haloalkoxy groups), (7) alkylcarbonyl groups, (8) alkoxycarbonyl groups, (9) optionally substituted aroyl groups (their substituents include, for example, halogen atoms, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups and C₁₋₃ alkylenedioxy groups), (10) cycloalkylalkyl groups, (11) isoxazolyl group, and (12) optionally substituted adamantyl groups (their substituents include, for example, hydroxyl group).

Specific examples of the “optionally substituted carbamoyl group” are carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, phenylcarbamoyl, phenylmethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopropylmethylcarbamoyl, cyclohexylmethylcarbamoyl, 2,3-dihydroxypropylcarbamoyl, tetrahydrofuranylalkylcarbamoyl, methoxyethylcarbamoyl, trifluoroethylcarbamoyl, adamantylcarbamoyl, hydroxyadamantylcarbamoyl, etc.

The two substituents of the carbamoyl group may bind to each other to form a 4- to 6-membered aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen or sulfur, such as pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperazine (the nitrogen atom of this piperazine may be substituted by methyl, ethyl or propyl), or the like, and the carbamoyl group may be further substituted by a hydroxyl group.

Specific examples of such a substituted carbamoyl group are pyrrolidinocarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, 4-hydroxypiperidinocarbamoyl, etc.

The substituent(s) of the “optionally substituted nitrogen-containing saturated heterocyclic group” includes, for example,

(1) halogen atoms, (2) alkyl groups, (3) alkyl groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, perfluoroethyl and methoxyethyl), (4) alkoxy groups, (5) alkoxy groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy), (6) cyano group, and (7) oxo group.

When two R⁶s, R⁷s, R⁸ s or R⁹s are present, they may be present on one and the same carbon atom or may be present on different carbon atoms, respectively.

The phrase “two R⁶s, R⁷s, R⁸s or R⁹s, when taken together, represent methylene or ethylene and bind to one or more carbon atoms constituting the ring, to form a new ring” means that they form a spiro ring or a bicyclo ring through one and the same carbon atom or different carbon atoms, respectively.

The phrase “two R^(T)s, when taken together, represent methylene, ethylene, trimethylene, tetramethylene or butenylene and bind to one or two carbon atoms constituting the ring, to form a new ring” means that they form a spiro ring or a bicyclo ring through one and the same carbon atom or different carbon atoms, respectively.

The “haloalkoxy group” includes, for example, alkoxy groups of 1 to 4 carbon atoms substituted by a halogen atom(s). Specific examples thereof are fluoromethoxy, difluoromethoxy, trifluoromethoxy, etc.

The “haloalkyl group” includes, for example, alkyl groups of 1 to 4 carbon atoms substituted by a halogen atom(s). Specific examples thereof are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, perfluoroethyl, etc.

The “C₁₋₃ alkylenedioxy group” includes, for example, methylenedioxy, ethylenedioxy and trimethylenedioxy.

The “substituted alkyl group” for R^(4b) includes, for example, alkyl groups of 1 to 3 carbon atoms substituted by a cycloalkyl group of 3 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substituted aryl group (e.g. phenyl group). Specific examples thereof are benzyl, p-chlorobenzyl, p-methoxybenzyl, p-fluorobenzyl, cyclopentylmethyl, cyclohexymethyl, etc.

The “substituted alkenyl group” for R^(4b) includes, for example, alkenyl groups of 2 or 3 carbon atoms substituted by a cycloalkyl group of 5 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl or cycloheptyl) or an aryl group (e.g. phenyl group). Examples thereof are vinyl, propenyl, allyl, isopropenyl, etc., which are substituted by phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

The “alkenyloxy group” for R^(4b) includes, for example, linear or branched alkenyloxy groups of 2 to 8 carbon atoms. Specific examples thereof are allyloxy, isobutenyloxy, etc.

The “substituted alkoxy group” for R^(4b) includes, for example, alkoxy groups of 1 to 3 carbon atoms substituted by a cycloalkyl group of 3 to 7 carbon atoms (e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substituted aryl group (e.g. phenyl group). Specific examples thereof are benzyloxy, phenethyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentylmethyloxy, etc.

The “substituted alkenyloxy group” for R^(4b) includes, for example, alkenyloxy groups of 2 or 3 carbon atoms substituted by a cycloalkyl group of 3 to 7 carbon atoms (e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substituted aryl group (e.g. phenyl group). Examples thereof are vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc., which are substituted by phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

Specific examples of the “optionally substituted aryloxy group” for R^(4b) are phenoxy, p-nitrophenoxy, p-methoxyphenoxy, p-fluorophenoxy, naphthoxy, etc.

Specific examples of each of the “substituted alkoxycarbonyl group” and the group represented by the formula: -Rd-CO(O)—Re wherein Rd and Re are as defined above, are pivaloyloxymethoxycarbonyl, 1-(pivaloyloxy)ethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, 5-(tert-butyl)-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethyloxycarbonyl, propyloxymethoxycarbonyl, n-butoxymethoxycarbonyl, isobutoxymethoxycarbonyl, 1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(tert-butoxycarbonyloxy)ethoxycarbonyl, 1-(acetyloxy)ethoxycarbonyl, 1-(isobutoxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, 1-(cyclohexylcarbonyloxy)ethoxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, 1-(cyclopentylcarbonyloxy)ethoxycarbonyl, etc.

The substituent(s) of each of the “optionally substituted alkyl group” and the “optionally substituted alkoxy group” for Rc includes, for example, halogen atoms, alkoxy groups and cycloalkyl groups.

The substituent(s) of the “optionally substituted heteroarylamino group” for Rc includes those exemplified as the substituents of (7) the “optionally substituted heteroaryl groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.

As the “alkylene group” for Rd, there are exemplified the above-exemplified ones, preferably methylene.

As the “alkenylene group” for Rd, there are exemplified the above-exemplified ones, preferably vinylene.

As the “prodrug”, there are exemplified those which can easily be hydrolyzed in a living body to regenerate the compound (1) of the present invention. Specific examples thereof are compounds obtained by converting the amino group of the compound represented by the formula (I) to —NHQ^(X). Here, the following are exemplified as Q^(X):

(1)

(2) —COR³³ (3) —COO—CR³⁴ (R³⁵)—OCOR³⁶ (4) —COOR³⁷

wherein R³³ is a hydrogen atom, an alkyl group or an optionally substituted aryl group; R³⁴ and R³⁵ are independently a hydrogen atom or an alkyl group; R³⁶ is a hydrogen atom, an alkyl group, an aryl group or a benzyl group; and R³⁷ is an alkyl group or a benzyl group.

Preferable examples of Q^(X) are the group of (1) and the groups of (3). Preferable examples of the groups of (3) are groups in which R³⁴ is a hydrogen atom, R³⁵ is a hydrogen atom, methyl or ethyl and R³⁶ is methyl or ethyl. These compounds may be produced according to conventional processes (for example, J. Med. Chem. 35, 4727 (1992) and WO 01/40180). In addition, the prodrug may be one which is converted to the original compound under physiological conditions, such as those described in “Development of Medicines Vol. 7, Molecular Design”, pp. 163-198, Hirokawa Shoten, 1990.

As the “pharmaceutically acceptable salt”, there are exemplified inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, etc., and organic acid salts such as acetic acid salt, propionic acid salt, oxalic acid salt, succinic acid salt, lactic acid salt, malic acid salt, tartaric acid salt, citric acid salt, maleic acid salt, fumaric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic acid salt, ascorbic acid salt, etc.

In addition, the present invention includes compounds represented by the formula (I), prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs. The present invention also includes their hydrates or solvates (e.g. ethanol solvates). Furthermore, the present invention includes all tautomers, all existing stereoisomers and all crystal forms of the compound (1) of the present invention.

Preferable examples of the compound of the present invention are the following compounds. In the compounds listed in the following tables, the following abbreviations are used in some cases for the simplification of description.

2-Py: 2-pyridyl group, 3-Py: 3-pyridyl group, 4-Py: 4-pyridyl group, Ph: phenyl group, Et: ethyl group, Me: methyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, n-Bu: n-butyl group, t-Bu: tert-butyl group, Bn: benzyl group, Ac: acetyl group, cycpro: cyclopropyl group, cycbu: cyclobutyl group, cychex: cyclohexyl group, etoet: ethoxyethyl group, meoet: methoxyethyl group, f2etoet: 2,2-difluoroethoxyethyl group, f2meoet: difluoromethoxyethyl group, cycprooet: cyclopropyloxyethyl group, isoproet: isopropoxyethyl group, ms: methanesulfonyl group, etomet: ethoxymethyl group, meomet: methoxymethyl group, f2meomet: difluoromethoxymethyl group, and f2etomet: 2,2-difluoroethoxymethyl group.

The following abbreviations for partial structures are used in some cases.

[Formula 17]

No. Y R²  1 Q1 Q13  2 Q2 Q13  3 Q79 Q13  4 Q80 Q13  5 Q81 Q13  6 Q82 Q13  7 Q83 Q13  8 Q84 Q13  9 Q85 Q13 10 Q86 Q13 11 Q87 Q13 12 Q88 Q13 13 Q89 Q13 14 Q90 Q13 15 Q91 Q13 16 Q92 Q13 17 Q98 Q13 18 Q1 Q3 19 Q1 Q4 20 Q1 Q5 21 Q1 Q6 22 Q1 Q7 23 Q1 Q8 24 Q1 Q9 25 Q1 Q10 26 Q1 Q11 27 Q1 Q12 28 Q1 Q13 29 Q1 Q14 30 Q1 Q15 31 Q1 Q16 32 Q1 Q17 33 Q1 Q18 34 Q1 Q19 35 Q1 Q20 36 Q1 Q21 37 Q1 Q22 38 Q1 Q23 39 Q1 Q24 40 Q2 Q3 41 Q2 Q4 42 Q2 Q5 43 Q2 Q6 44 Q2 Q7 45 Q2 Q10 46 Q1 Q26 47 Q1 Q27 48 Q114 Q13 49 Q115 Q13 50 Q116 Q13 51 Q117 Q13 52 Q118 Q13

No. R¹ R² R⁵ 53 Q35 Q4 Me 54 Q36 Q5 Me 55 Q37 Q13 Me 56 Q38 Q4 Me 57 Q39 Q5 Me 58 H Q13 Me 59 Q47 Q4 Me 60 Q48 Q5 Me 61 Q54 Q13 Me 62 Q56 Q4 Me 63 Q57 Q5 Me 64 Q58 Q13 Me 65 Q59 Q4 Me 66 Q60 Q5 Me 67 Q61 Q13 Me 68 Q62 Q4 Me 69 Q63 Q5 Me 70 Q64 Q13 Me 71 Q65 Q4 Me 72 Q66 Q5 Me 73 Q67 Q13 Me 74 Q68 Q4 Me 75 Q69 Q5 Me 76 Q70 Q13 Me 77 Q71 Q4 Me 78 Q72 Q5 Me 79 Q73 Q4 Me 80 Q74 Q5 Me 81 Q75 Q13 Me 82 Q76 Q4 Me 83 Q77 Q5 Me 84 Q78 Q13 Me 85 Q119 Q4 Me 86 Q120 Q5 Me 87 Q121 Q13 Me 88 Q122 Q4 Me 89 Q77 Q5 Me 90 Q78 Q13 Me 91 Me Q4 etoet 92 Me Q5 meoet 93 Me Q13 f2etoet 94 Me Q4 f2meoet 95 Me Q5 cycproet 96 Me Q13 isoproet 97 Me Q4 etomet 98 Me Q5 meomet 99 Me Q13 f2meomet 100  Me Q13 Q144 101  Me Q13 Q145 102  Me Q13 Q146 103  Me Q13 Q147 104  Me Q13 Q148

[Formul 18]

No. R¹ R² R³ R⁵ Y 105 Me Q13 Ac Me Q1 106 Me Q13 Me Me Q1 107 Me Q13 Et Me Q1 108 Me Q5 etomet Me Q1 109 Me Q5 meomet Me Q1 110 Me Q5 f2meomet Me Q1 111 Me Q13 Q149 Me Q1 112 Me Q13 Q123 Me Q1 113 Me Q13 CO₂H Me Q1 114 Me Q13 Q135 Me Q1 115 Me Q13 Q136 Me Q1 116 Me Q13 Q137 Me Q1 117 Me Q13 Q138 Me Q1 118 Me Q13 Q139 Me Q1 119 Me Q13 Q140 Me Q1 120 Me Q13 Q141 Me Q1 121 Me Q13 Q142 Me Q1 122 Me Q13 Q143 Me Q1 123 Me Q13 Q124 Me Q1 124 Me Q5 Q125 Me Q1 125 Me Q13 Q126 Me Q1 126 Me Q4 Q127 Me Q1 127 Me Q13 etomet Me Q2 128 Me Q13 meomet Me Q118 129 Me Q4 Q103 Me Q1 130 Me Q13 Q49 Me Q1 131 Me Q4 Q49 Me Q1 132 Me Q5 Q50 Me Q1 133 Me Q13 Q51 Me Q1 134 H Q13 Q52 Me Q1 135 Me Q5 Q53 Me Q1 136 Me Q13 Q54 Me Q1 137 Me Q4 Q56 Me Q1 138 Me Q5 Q128 Me Q1 139 Me Q13 Q129 Me Q1 140 Me Q4 Q130 Me Q1 141 Me Q5 Q131 Me Q1 142 Me Q13 Q132 Me Q1 143 Q66 Q13 etomet Me Q1 144 Q67 Q5 meomet Me Q1 145 Q68 Q13 etomet Me Q1 146 Q69 Q13 etomet Me Q1 147 Me Q5 Ac Me Q2 148 Me Q13 Me Me Q2 149 Q65 Q5 Et Me Q2 150 Me Q5 CN Me Q2 151 Me Q13 meomet Me Q2 152 Me Q5 f2meomet Me Q2 153 Me Q5 isoproet Me Q2 154 Me Q13 cycproet Me Q2 155 H Q5 Q50 Me Q2 156 Me Q5 Q27 Me Q2

[Formula 19]

No. T²¹ R² Y 157 3-OCHF₂ Q13 Q1 158 3-OEt Q13 Q1 159 3-O(i-Pr) Q13 Q1 160 3-Q150 Q5 Q1 161 3-Q151 Q5 Q1 162 3-OMe/5-OMe Q5 Q1 163 4-OCHF₂ Q13 Q1 164 2-OCHF₂ Q13 Q1 165 2-Q132 Q13 Q1 166 3-OCHF₂ Q5 Q2 167 3-OEt Q5 Q2 168 3-O(i-Pr) Q5 Q2 169 3-Q150 Q13 Q2 170 3-Q151 Q5 Q2 171 3-OMe/5-OMe Q13 Q2 172 CO₂H Q5 Q2 173 2-Q132 Q14 Q118 174 2-OMe Q13 Q118 175 3-OCHF₂ Q13 Q114 176 3-OEt Q5 Q115 177 3-O(i-Pr) Q13 Q83 178 3-Q150 Q4 Q84 179 3-Q151 Q13 Q85 180 4-Q135 Q13 Q1 181 4-OCHF₂ Q4 Q87 182 H Q13 Q1

No. R² R⁴ 183 Q4 CN 184 Q5 CF₃ 185 Q13 Ph 186 Q13 Ac 187 Q13 CO₂H 188 Q13 Q135 189 Q13 Q136 190 Q13 Q137 191 Q13 Q138 192 Q13 Q139 193 Q13 Q140 194 Q13 Q141 195 Q13 Q142 196 Q13 Q143 197 Q13 Q129 198 Q13 Q130 199 Q5 Q132 200 Q13 i-Pr 201 Q5 EtO 202 Q5 Q50 203 Q13 Q46 204 Q5 Q152 205 Q5 Q111 206 Q13 Q110 207 Q5 NMe₂ 208 Q5 Q34

[Formula 20]

No. T²¹ R³ 209 3-OCHF₂ Ac 210 3-OEt Me 211 3-O(i-Pr) Et 212 3-Q150 CN 213 3-Q151 Q50 214 3-OMe/5-OMe Q52 215 4-OCHF₂ Q54 216 2-OCHF₂ Q128 217 2-Q132 Q129 218 3-OCHF₂ Q130 219 3-OEt Q131 220 3-O(i-Pr) Q132 221 3-Q150 etomet 222 3-Q151 meomet 223 3-OMe/5-OMe etomet 224 4-OCHF₂ etomet 225 2-Q132 f2meomet 226 2-OMe isoproet 227 3-OCHF₂ cycproet 228 3-OEt Q149 229 3-O(i-Pr) Q123 230 3-OEt CO₂H 231 3-OEt Q135 232 3-OEt Q136 233 3-OEt Q137 234 3-OEt Q138 235 3-OEt Q139 236 3-OEt Q140 237 3-OEt Q141 238 3-OEt Q142 239 3-OEt Q143

[Formula 21]

No. T²² 240 3-CO₂H 241 3-Q135 242 3-Q136 243 3-Q137 244 3-Q138 245 3-Q139 246 3-Q140 247 3-Q141 248 3-Q142 249 3-Q143 250 4-CO₂H 251 4-Q135 252 4-Q136 253 4-Q137 254 4-Q138 255 4-Q139 256 4-Q140 257 4-Q141 258 4-Q142 259 4-Q143

No. T²³ 260 3-CO₂H 261 3-Q135 262 3-Q136 263 3-Q137 264 3-Q138 265 3-Q139 266 3-Q140 267 3-Q141 268 3-Q142 269 3-Q143 270 4-CO₂H 271 4-Q135 272 4-Q136 273 4-Q137 274 4-Q138 275 4-Q139 276 4-Q140 277 4-Q141 278 4-Q142 279 4-Q143

[Formula 22]

No. T²⁴ 280 2-CO₂H 281 2-Q135 282 2-Q136 283 2-Q137 284 2-Q138 285 2-Q139 286 2-Q140 287 2-Q141 288 2-Q142 289 2-Q143 290 3-CO₂H 291 3-Q135 292 3-Q136 293 3-Q137 294 3-Q138 295 3-Q139 296 3-Q140 297 3-Q141 298 3-Q142 299 3-Q143 300 4-CO₂H 301 4-Q135 302 4-Q136 303 4-Q137 304 4-Q138 305 4-Q139 306 4-Q140 307 4-Q141 308 4-Q142 309 4-Q143

[Formula 23]

No. T²⁵ Y 310 2-CO₂H Q1 311 2-Q135 Q1 312 3-CO₂H Q1 313 3-Q135 Q1 314 4-CO₂H Q1 315 4-Q135 Q1 316 2-CN Q1 317 3-CN Q1 318 4-CN Q1 319 2-CO₂H Q118 320 2-Q135 Q118 321 3-CO₂H Q118 322 3-Q135 Q118 323 4-CO₂H Q118 324 4-Q135 Q118 325 2-CN Q118 326 3-CN Q118 327 4-CN Q118

[Formula 24]

No. T²⁶ Y 328 3-CN/5-CO₂H Q1 329 3-CN/5-Q135 Q1 330 2-CN/5-CO₂H Q1 331 2-CN/5-Q135 Q1 332 4-CN/5-CO₂H Q1 333 4-CN/5-Q135 Q1 334 2-CN Q1 335 3-CN Q1 336 4-CN Q1 337 2-CO₂H Q118 338 2-Q135 Q118 339 3-CO₂H Q118 340 3-Q135 Q118 341 4-CO₂H Q118 342 4-Q135 Q118 343 2-CN Q118 344 3-CN Q118 345 4-CN Q118

[Formula 25]

No. T²⁷ 346 4-CN 347 3-CN 348 4-CO₂H 349 4-Q135 350 3-CO₂H 351 3-Q135

[Formula 26]

No. T²⁸ 352 2-CN 353 3-CN 354 2-CO₂H 355 2-Q135 356 3-CO₂H 357 3-Q135

[Formula 27]

No. R² R³ 358 Q6 Q153 359 Q6 Q154 360 Q6 Q155 361 Q13 Q156 362 Q13 Q157 363 Q6 Q158 364 Q6 Q159 365 Q6 Q160 366 Q13 Q161

When the portion corresponding to Y described in the item [1] is an unsubstituted or substituted 3-aminopyrrolidin-1-yl group, an unsubstituted or substituted 3-aminopiperidin-1-yl group or an unsubstituted or substituted (3-amino)hexahydroazepin-1-yl group in the above compounds having compound numbers 1 to 366, bicyclic pyrrole derivatives are more preferable in which the amino group at the 3-position is in an absolute configuration represented by the following formula (F₁):

wherein m1 and R⁶ are as defined in the item [1].

When the portion corresponding to Y described in the item [1] is an unsubstituted or substituted (2-aminocycloalkyl)amino group in the above compounds having compound numbers 1 to 366, compounds are more preferable in which the amino groups at the 1-position and 2-position are in an absolute configuration represented by the following formula (F₂) or (F₃)

wherein m2 and R⁷ are as defined in the item [1].

In addition, compounds are still more preferable in which the amino groups at the 1-position and 2-position are in an absolute configuration represented by the following formula (F₄):

wherein m2 and R⁷ are as defined in the item [1].

In the following description, a bond shown by a wedge-shaped solid line or broken line as in the formula (J₁) and formula (J₂) indicates an absolute configuration relating to an amino group, and a bond shown by a thick line as in the formula (J₃) indicates a relative configuration relating to an amino group (for example, the formula (J₃) represents a (±)-cis form).

wherein m2 and R⁷ are as defined in the item [1]

Of the above compounds having compound numbers 1 to 366 as the compound of the formula (I) described in the item [1], compounds containing in the formula “an alkoxycarbonyl group”, “an optionally substituted alkoxycarbonyl group”, “an optionally substituted cycloalkoxycarbonyl group”, “an optionally substituted aryloxycarbonyl group”, “an optionally substituted aralkyloxycarbonyl group” or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined above, are such that such a substituent is converted to “a carboxyl group” in some cases under physiological conditions in a living body by oxidation, reduction, hydrolysis or the like by an enzyme, or hydrolysis by acid in the stomach, or the like.

A process for producing the compound represented by the formula (I) of the present invention is explained below with reference to examples, which should not be construed as limiting the scope of the invention. In the present description, the following abbreviations are used in some cases for the simplification of description.

-   Boc: tert-butoxycarbonyl group -   Cbz: benzyloxycarbonyl group -   TMS: trimethylsilyl group -   TBS: tert-butyldimethylsilyl group -   SEM: 2-[(trimethylsilyl)ethoxy]methyl group -   Ac: acetyl group -   Me: methyl group -   Et: ethyl group -   Pr: propyl group -   i-Pr: isopropyl group -   Bu: butyl group -   i-Bu: isobutyl group -   t-Bu: tert-butyl group -   Ph: phenyl group -   Bn: benzyl group -   Ms: methanesulfonyl group -   TFA: trifluoroacetic acid -   Alloc: allyloxycarbonyl group

The compound represented by the formula (I) may be synthesized from a well-known compound by a combination of well-known synthesis processes. It may be synthesized, for example, by any of the following processes.

Production Process 1

A compound represented by the formula (1-17) or a salt thereof is produced, for example, by the following process:

wherein R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁹, m¹, m², m³, m⁴ and m⁵ are as defined above; X¹ is a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy); R⁵¹ is Alloc, N═C(Ph)₂, NHBoc, NHCbz or the following formula (G1):

R⁵² is Alloc, Boc or Cbz; and Y¹ is the protected state of the primary or secondary amino group in Y described in the item [1].

1) Step 1

A compound (1-8) may be produced by reacting a compound (1-1) with a compound selected from a compound (1-2), a compound (1-3), a compound (1-4), a compound (1-5), a compound (1-6) and a compound (1-7) in an inert solvent in the presence or absence of a base. The base includes, for example, organic bases (e.g. 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine and picoline), and inorganic bases (e.g. sodium ethoxide, sodium methoxide, potassium tert-butoxide and sodium hydride). The amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (1-1). The amount of the compound (1-2), compound (1-3), compound (1-4), compound (1-5), compound (1-6) or compound (1-7) used is usually chosen in the range of 1 to 2 equivalents per equivalent of the compound (1-1). The inert solvent includes, for example, alcohol solvents (e.g. methanol, ethanol and 2-propanol), ether solvents (tetrahydrofuran and 1,4-dioxane), and mixed solvents thereof. The reaction temperature may be chosen in the range of about 50° C. to about 120° C.

The compound (1-2) may be produced by the process described in the production process 19 described hereinafter, the compound (1-3) by the process described in the production process 20 described hereinafter, and the compound (1-5) by the process described in the production process 21 described hereinafter. As the compound (1-6), a commercial reagent may be used, or the compound (1-6) may be produced by the process described in literature (for example, Synthesis 391 (1994), Org. Lett. 5, 1591 (2003), Synthesis 1065 (1992), Synlett 755 (2002), J. Org. Chem. 56, 3063 (1991), J. Org. Chem. 60, 4177 (1995) and J. Org. Chem. 57, 6653 (1992)). The compound (1-7) may be produced by the same process as that described in literature (for example, J. Org. Chem. 61, 6700 (1996)) or the like.

2) Step 2

A compound (1-10) is produced by reacting the compound (1-8) with a compound (1-9) in an inert solvent. The amount of the compound (1-9) used is usually chosen in the range of 1 equivalent to excess equivalents per equivalent of the compound (1-8). The inert solvent includes, for example, organic bases (e.g. 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine and picoline), alcohol solvents (e.g. methanol, ethanol and 2-propanol), acetic acid, and mixed solvent thereof. The reaction temperature is chosen in the range of about 50° C. to about 150° C. and the reaction is usually carried out with refluxing.

3) Step 3

A compound (1-12) may be produced by reacting the compound (1-10) with a compound (1-11) in an inert solvent in the presence or absence of a base (see, for example, J. Heterocycl. Chem. 37, 1033 (2000), J. Chem. Soc., Perkin Trans. 1, 13, 1833 (1999) and J. Med. Chem. 38, 3838 (1995)). The amount of the compound (1-11) used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (1-10). The base includes, for example, alkali carbonates (e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate), alkali hydrides (e.g. sodium hydride and potassium hydride), and alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide). A suitable example thereof is potassium carbonate. The amount of the base used is usually chosen in the range of 1 to 3 equivalents per equivalent of the compound (1-10). The inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof. Suitable examples thereof are N,N-dimethylformamide and dimethyl sulfoxide. The reaction temperature may be chosen in the range of about 10° C. to about 180° C.

4) Step 4

A compound (1-13) may be produced by reacting the compound (1-12) with a base in an inert solvent (see, for example, WO02/068420). The base includes alkali hydrides (e.g. sodium hydride and potassium hydride) and the like. A suitable example thereof is sodium hydride. The amount of the base used is usually chosen in the range of 1 to 3 equivalents per equivalent of the compound (1-12). The inert solvent includes N,N-dimethylformamide, ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), and mixed solvents thereof. A suitable example thereof is tetrahydrofuran. The reaction temperature may be chosen in the range of about 10° C. to about 100° C.

5) Step 5

A compound (1-15) may be produced from the compound (1-13) by carrying out the following reactions (1) to (3).

(1) The compound (1-13) is reacted with a compound (1-14) in pyridine in the presence of a base. The reaction temperature may be chosen in the range of about 50° C. to about 160° C. The amount of the compound (1-14) used is usually chosen in the range of 1 to 5 equivalents. (2) A base is added to the reaction mixture obtained in the above item (1) and the reaction is carried out. The base includes cesium carbonate, potassium carbonate, sodium carbonate, etc. The amount of the base used is usually chosen in the range of 1 to 5 equivalents. The reaction temperature is chosen in the range of about 50° C. to about 160° C. (3) Methyl iodide is added to the reaction mixture obtained in the above item (2) and the reaction is carried out. The amount of methyl iodide used is usually chosen in the range of 1 to 5 equivalents. The reaction temperature is chosen in the range of about 10° C. to about 40° C.

6) Step 6

In this step 6, the following production process (A) or production process (B) may be adopted. Production process (A): A compound (1-16) may be produced by reacting the compound (1-15) with a mixture of sodium tungstate and an aqueous hydrogen peroxide solution in an inert solvent. The inert solvent includes alcohol solvents (e.g. ethanol, methanol and 2-propanol), organic acids (e.g. acetic acid and propionic acid), etc. A mixed solvent of the alcohol solvent and the organic acid is usually used as the inert solvent. The amount of sodium tungstate used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (1-15). The amount of the aqueous hydrogen peroxide solution (usually a 30% aqueous solution) used is usually chosen in the range of 10 to 100 equivalents per equivalent of the compound (1-15). The reaction temperature may be chosen in the range of about −10° C. to about 70° C. Production process (B): A compound (1-16) may be produced by reacting the compound (1-15) with Oxon (a registered trade name; Aldrich) in an inert solvent. The inert solvent includes alcohol solvents (e.g. ethanol, methanol and 2-propanol), etc. The amount of Oxon (a registered trade name; Aldrich) used is usually chosen in the range of 1 to 20 equivalents per equivalent of the compound (1-15). The reaction temperature may be chosen in the range of about −10° C. to about 70° C.

7) Step 7

The compound (1-17) may be produced from the compound (1-16) by the same process as in the step 2 described in production process 2.

Production Process 2

Each of compounds of the formula (2-2) and the formula (2-5) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², R⁴, X¹, Y¹ and Y are as defined above.

1) Step 1

A compound (2-1) may be produced by reacting a compound (1-16) with a base in an inert solvent. The base includes, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate, etc. A suitable example thereof is sodium hydroxidec. The amount of the base used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (1-16). The inert solvent includes, for example, water, alcohol solvents (e.g. methanol, ethanol and 2-propanol), tetrahydrofuran, and mixed solvents thereof. The reaction temperature is chosen in the range of about 50° C. to about 100° C.

In this step, a compound in which a protective group for the primary amino group or secondary amino group in Y has been removed is produced in some cases. The compound (2-1) in which the primary amino group or secondary amino group in Y has been protected again with a protective group (e.g. Boc or Cbz) may be produced by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).

2) Step 2

The compound (2-2) may be produced from the compound (2-1) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.

3) Step 3

A compound (2-4) may be produced by reacting the compound (2-1) with a compound (2-3) in an inert solvent in the presence of a base. The amount of the compound (2-3) used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (2-1). The base includes, for example, alkali carbonates (e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate), alkali hydrides (e.g. sodium hydride and potassium hydride), and alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide). A suitable example thereof is potassium carbonate. The amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (2-1). The inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof. A suitable example thereof is N,N-dimethylformamide. The reaction temperature may be chosen in the range of about 0° C. to about 180° C.

4) Step 4

The compound (2-5) may be produced from the compound (2-4) by the same process as in the above step 2.

Production Process 3

A compound of the formula (3-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above, and R⁵⁴O is “an optionally substituted alkoxy group”, “an optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group” or “an optionally substituted cycloalkyloxy group”.

1) Step 1

A compound (3-2) may be produced by reacting a compound (1-16) with a compound (3-1) in an inert solvent in the presence of a base. The base includes potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium phenoxide, potassium phenoxide, sodium hydride, etc. A suitable example thereof is sodium hydride. The amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (3-1). The inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc. The reaction temperature may be chosen in the range of about −10° C. to about 50° C.

2) Step 2

The compound (3-3) may be produced from the compound (3-2) by the same process as in the step 2 described in production process 2.

Production Process 4

A compound of the formula (4-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above, and R⁵⁵s is “an optionally substituted alkylthio group” or “an optionally substituted arylthio group”.

1) Step 1

A compound (4-2) may be produced from a compound (1-16) by the same process as in the step 1 described in production process 3.

2) Step 2

The compound (4-3) may be produced from the compound (4-2) by the same process as in the step 2 described in production process 2.

Production Process 5

Each of compounds of the formula (5-2) and the formula (5-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above.

1) Step 1

A compound (5-1) may be produced by reacting a compound (1-16) with sodium cyanide or potassium cyanide in an inert solvent. The amount of sodium cyanide or potassium cyanide used is usually chosen in the range of 0.8 to 5 equivalents per equivalent of the compound (1-16). The inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc. The reaction temperature may be chosen in the range of about 10° C. to about 100° C.

2) Step 2

The compound (5-2) may be produced from the compound (5-1) by the same process as in the step 2 described in production process 2.

3) Step 3

A compound (5-3) may be produced by reacting the compound (5-1) with an aqueous hydrogen peroxide solution in an inert solvent in the presence of a base. The base includes, for example, inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc. The amount of the base used is usually chosen in the range of 0.5 to 10 equivalents per equivalent of the compound (5-1). The amount of the aqueous hydrogen peroxide solution used is usually chosen in the range of 1 to 20 equivalents per equivalent of the compound (5-1). The inert solvent includes dimethyl sulfoxide, acetone, etc. A suitable example thereof is dimethyl sulfoxide. The reaction temperature may be chosen in the range of about 1° C. to about 100° C.

4) Step 4

The compound (5-4) may be produced from the compound (5-3) by the same process as in the step 2 described in production process 2.

Production Process 6

A compound of the formula (6-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above, and R⁵⁶R⁵⁷N is “an optionally substituted nitrogen-containing saturated heterocyclic group” or “an optionally substituted amino group”.

1) Step 1

A compound (6-2) may be produced by reacting a compound (1-16) with a compound (6-1) in the presence or absence of an inert solvent. The amount of the compound (6-1) used is usually chosen in the range of 1 to 100 equivalents per equivalent of the compound (1-16). When the compound (6-1) is liquid, it may be used also as a solvent. The inert solvent includes alcohol solvents (e.g. ethanol, methanol and 2-propanol), etc. The reaction temperature may be chosen in the range of about 50° C. to about 150° C.

2) Step 2

The compound (6-3) may be produced from the compound (6-2) by the same process as in the step 2 described in production process 2.

Production Process 7

A compound of the formula (7-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above; R¹⁸ is “an optionally substituted alkyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted heteroarylalkyl group” or “an optionally substituted aralkyl group”; and M¹ is lithium, magnesium chloride or magnesium bromide.

1) Step 1

A compound (7-2) may be produced by reacting a compound (1-16) with a compound (7-1) in an inert solvent. The amount of the compound (7-1) used is usually chosen in the range of 1 to 10 equivalents per equivalent of the compound (1-16). The inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc. The reaction temperature may be chosen in the range of about −10° C. to about 50° C.

2) Step 2

The compound (7-3) may be produced from the compound (7-2) by the same process as in the step 2 described in production process 2.

Production Process 8

A compound of the formula (8-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above, and R⁵⁹C(O) is “an optionally substituted aroyl group”, “an optionally substituted heteroarylcarbonyl group” or “an optionally substituted alkylcarbonyl group”.

1) Step 1

A compound (8-2) may be produced by reacting a compound (1-16) with a compound (8-1) in an inert solvent in the presence of a base. The amount of the compound (8-1) used is usually chosen in the range of 1 to 10 equivalents per equivalent of the compound (1-16). The base includes sodium hydride, etc. The inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc. The reaction temperature may be chosen in the range of about 50° C. to about 150° C.

2) Step 2

The compound (8-3) may be produced from the compound (8-2) by the same process as in the step 2 described in production process 2.

Production Process 9

A compound of the formula (9-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², R⁴, Y¹ and Y are as defined above, and X³ is a leaving group (e.g. an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy).

1) Step 1

When R² in the item [4] is a group of any of the formula (E), formula (F), formula (G) and formula (H), a compound (9-1) may be produced from a compound (2-4) by the following process 1.

Process 1

A compound (9-1) may be produced by reacting a compound (2-4) with an acid in an inert solvent. The acid includes inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc. A suitable example thereof is sulfuric acid. The amount of the acid used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (2-4). The inert solvent includes water and the like. The reaction temperature is chosen in the range of about 50° C. to about 200° C.

In this step, a compound in which a protective group for the primary amino group or secondary amino group in Y has been removed is produced in some cases. The compound (9-1) in which the primary amino group or secondary amino group in Y has been protected again with a protective group (e.g. Boc or Cbz) may be produced by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).

When R² in the item [4] is a group of either the formula (I) or the formula (J), a compound (9-1) may be produced from a compound (2-4) by the following process 2 [(1) (2)].

Process 2

(1) R² of the compound (2-4) is removed by the same method as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), Tetrahedron 27, 5523 (1971) and Aus. J. Chem. 22, 1321 (1969)) or the like.

(2) The same reaction as in the process 1 in the step 1 described in production process 9 is carried out.

2) Step 2

A compound (9-3) may be produced from the compound (9-1) by the same process as that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, Bioorg. Med. Chem. Lett. 11, 1993 (2001), Organic Letters 4, 4033 (2002), Organic Letters 5, 4987 (2003), Synlett 128 (2004), and J. Am. Chem. Soc. 124, 116847 (2002)) or the like.

When R² in the item [4] is a group of any of the formula (E), formula (F), formula (G) and formula (H), a compound (9-3) may be produced from the compound (9-1) by the same process as in the step 3 described in production process 1.

3) Step 3

The compound (9-4) may be produced from the compound (9-3) by the same process as in the step 2 described in production process 2.

Production Process 10

Each of compounds of the formula (10-6), formula (10-8) and formula (10-10) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², X³, Y¹ and Y are as defined above, and R⁶⁰ is the above-mentioned R⁵⁴O, R⁵⁵S or R⁵⁶R⁵⁷N.

1) Step 1

A compound (10-1) may be produced from a compound (2-1) by the same process as in the step 1 described in production process 9.

2) Step 2

A compound (10-2) may be produced from the compound (10-1) by the same production process as described in literature (for example, WO03/104229 and Chem. Pharm. Bull. 50, 1163 (2002)).

3) Step 3

A compound (10-3) may be produced from the compound (10-2) by the same process as in the step 2 described in production process 9.

4) Step 4

A compound (10-5) may be produced from the compound (10-3) by the same process as in the step 1 described in production process 3, the step 1 described in production process 4 or the step 1 described in production process 6.

5) Step 5

The compound (10-6) may be produced from the compound (10-5) by the same process as in the step 2 described in production process 2.

6) Step 6

A compound (10-7) may be produced from the compound (10-3) by the same process as in the step 1 described in production process 5.

7) Step 7

The compound (10-8) may be produced from the compound (10-7) by the same process as in the step 2 described in production process 2.

8) Step 8

A compound (10-9) may be produced from the compound (10-7) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, WO03/104229 and WO03/104229).

In this step, a compound in which a protective group for the primary amino group or secondary amino group in Y has been removed is produced in some cases. The compound (10-9) in which the primary amino group or secondary amino group in Y has been protected again with a protective group (e.g. Boc or Cbz) may be produced by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).

9) Step 9

The compound (10-10) may be produced from the compound (10-9) by the same process as in the step 2 described in production process 2.

Production Process 11

A compound of the formula (11-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R¹, R², Y¹ and Y are as defined above, and R⁶¹ is “an optionally substituted alkoxy group”, “an optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group”, “an optionally substituted cycloalkyloxy group”, “an optionally substituted alkylthio group”, “an optionally substituted arylthio group”, cyano, “an optionally substituted nitrogen-containing saturated heterocyclic group”, “an optionally substituted amino group”, “an optionally substituted alkyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted heteroarylalkyl group”, “an optionally substituted aralkyl group”, “an optionally substituted aroyl group”, “an optionally substituted heteroarylcarbonyl group” or “an optionally substituted alkylcarbonyl group”.

1) Step 1

A compound (11-1) may be produced by reacting a compound (10-3) with sodium methanethiol in an inert solvent in the presence or absence of a base. The base includes, for example, inorganic bases such as sodium hydride, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.; and organic bases such as 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine, picoline, etc. The amount of the base used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (10-3). The amount of sodium methanethiol used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (10-3). The inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof. The reaction temperature may be chosen in the range of about 10° C. to about 120° C.

2) Step 2

A compound (11-2) may be produced from the compound (11-1) by the same process as in the step 6 described in production process 1.

3) Step 3

A compound (11-3) may be produced from the compound (11-2) by the same process as in the step 1 described in production process 3, the step 1 described in production process 4, the step 1 described in production process 5, the step 1 described in production process 6, the step 1 described in production process 7 or the step 1 described in production process 8.

4) Step 4

The compound (11-4) may be produced from the compound (11-3) by the same process as in the step 2 described in production process 2.

Production Process 12

Each of compounds of the formula (12-3) and the formula (12-5) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², Y¹ and Y are as defined above; a compound of the formula (12-1) includes the compound (9-3) described in production process 9 and the compound (11-3) described in production process 11; L1 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; and R⁶² is “an optionally substituted alkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted alkynyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted aralkyl group” or “an optionally substituted heteroarylalkyl group”.

1) Step 1

A compound (12-2) may be produced from a compound (12-1) by the same production process as described in literature (for example, Synth. Commun. 33, 2671 (2003), Tetrahedron Letters 42, 863 (2001), Synthesis 926 (1995), Tetrahedron Letters 37, 1095 (1996), J. Org. Chem. 64, 5366 (1999), Indian J. Chem., Sect B 35, 141 (1996) and J. Heterocycl. Chem. 24, 1313 (1987)).

2) Step 2

The compound (12-3) may be produced from the compound (12-2) by the same process as in the step 2 described in production process 2.

3) Step 3

A compound (12-4) may be produced from the compound (12-2) by the same production process as described in literature (for example, Chem. Rev. 95, 2457 (1995), Chem. Rev. 103, 1979 (2003), Chem. Rev. 100, 3009 (2000), Organic Process Research & Development 5, 254 (2001), J. Med. Chem. 45, 999 (2002), Synthesis 563 (1997), J. Org. Chem. 65, 9001 (2000), J. Org. Chem. 64, 4196 (1999), J. Org. Chem. 67, 3904 (2002), Adv. Synth. Catal. 345, 620 (2003) and J. Med. Chem. 43, 675 (2000)).

4) Step 4

The compound (12-5) may be produced from the compound (12-4) by the same process as in the step 2 described in production process 2.

Production Process 13

A compound of the formula (13-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², M, Y¹ and Y are as defined above; a compound of the formula (12-1) is as described above; and R⁶³ is “an optionally substituted alkyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted aryl group” or “an optionally substituted heteroaryl group”.

1) Step 1

A compound (13-1) may be produced from a compound (12-1) by the same production process as described in literature (for example, J. Heterocycl. Chem. 30, 957 (1993), Chem. Pharm. Bull. 42, 237 (1994), Aust. J. Chem. 47, 1009 (1994) and J. Heterocycl. Chem. 12, 517 (1975)).

2) Step 2

A compound (13-3) may be produced from the compound (13-1) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

As a compound (13-2), a commercial one may be used, or the compound (13-2) may be produced by the process described, for example, in Japanese Chemical Association, Jikken Kagaku Koza (Experimental Chemistry) Vol. 25, Maruzen Co., Ltd.

3) Step 3

The compound (13-4) may be produced from the compound (13-3) by the same process as in the step 2 described in production process 2.

Production Process 14

A compound of the formula (14-2) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², R⁶³, Y¹ and Y are as defined above.

1) Step 1

A compound (14-1) may be produced from a compound (13-3) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

2) Step 2

The compound (14-2) may be produced from the compound (14-1) by the same process as in the step 2 described in production process 2.

Production Process 15

A compound of the formula (15-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A¹, R¹, R², Y¹ and Y are as defined above; R⁶⁴O is “an optionally substituted alkoxy group”, “an optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group” or “an optionally substituted cycloalkyloxy group”; and X² is a hydroxyl group or a leaving group (e.g. an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy).

1) Steps 1 to 2

A compound (15-3) may be produced from a compound (13-1) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989), Organic Reactions (New York) 42, 335-656 (1992), Tetrahedron Lett. 44, 4873 (2003) and J. Am. Chem. Soc. 125, 4978 (2003)).

2) Step 3

The compound (15-4) may be produced from the compound (15-3) by the same process as in the step 2 described in production process 2.

Production Process 16

A compound of the formula (16-2) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², R⁶³, Y¹ and Y are as defined above.

1) Step 1

A compound (16-1) may be produced from a compound (13-3) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989), J. Org. Chem. 65, 6179 (2000), J. Org. Chem. 58, 6913 (1993), Bull. Chem. Soc. Jpn. 67, 1107 (1994) and J. Org. Chem. 60, 2430 (1995).

2) Step 2

The compound (16-2) may be produced from the compound (16-1) by the same process as in the step 2 described in production process 2.

Production Process 17

A compound of the formula (17-2) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², Y¹ and Y are as defined above, and R⁶⁵C(O) is a carboxyl group, “an optionally substituted carbamoyl group”, “an optionally substituted alkoxycarbonyl group”, “an optionally substituted aryloxycarbonyl group”, “an optionally substituted aralkyloxycarbonyl group”, “an optionally substituted cycloalkyloxycarbonyl group”, “an optionally substituted alkylcarbonyl group”, “an optionally substituted heteroarylcarbonyl group”, “an optionally substituted aroyl group” or “an optionally substituted cycloalkylcarbonyl group”.

1) Step 1

A compound (17-1) may be produced from a compound (13-1) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989) and A. Hassner et al., Organic Synthesis Based On Name Reactions And Unnamed Reactions, Elsevier Science Ltd., (1994)).

In the case of a compound (17-1) in which R⁶⁵C(O) is “an optionally substituted alkoxycarbonyl group”, “an optionally substituted aryloxycarbonyl group”, “an optionally substituted aralkyloxycarbonyl group” or “an optionally substituted cycloalkyloxycarbonyl group”, this compound may be converted to another compound (17-1) in which R⁶⁵C(O) is a carboxyl group by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.

2) Step 2

The compound (17-2) may be produced from the compound (17-1) by the same process as in the step 2 described in production process 2.

Production Process 18

A compound of the formula (18-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², R³, X¹, Y¹ and Y are as defined above; CO₂H shown in a compound (18-1) indicates that R³ or R⁴ shown in the formula (I) is a carboxyl group or that a carboxyl group is present in the partial structure of R³, R⁴ or R⁵; and CO₂R⁶⁶ shown in a compound (18-3) and the compound (18-4) indicates a state in which the CO₂H of the compound (18-1) has been converted to CO₂R⁶⁶, and specifically, CO₂R⁶⁶ indicates, for example, the formula: C(O)O—Re wherein Re is as defined above.

1) Step 1

A compound (18-3) may be produced by reacting a compound (18-1) with a compound (18-2) in an inert solvent in the presence of a base. The amount of the compound (18-2) used is usually chosen in the range of 1 to 3 equivalents per equivalent of the compound (18-1). The base includes, for example, alkali carbonates (e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate), alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide), alkali hydrides (e.g. sodium hydride and potassium hydride), and alkoxyalkalis (e.g. potassium tert-butoxide). Suitable examples thereof are potassium carbonate and sodium hydride. The amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (18-1). The inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof. A suitable example thereof is N,N-dimethylformamide. The reaction temperature may be chosen in the range of about 10° C. to about 100° C.

As the compound (18-2), a commercial reagent may be used, or the compound (18-2) may be produced by the same production process as described in literature (for example, WO03/027098, WO00/06581, and R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

2) Step 2

The compound (18-4) may be produced from the compound (18-3) by the same process as in the step 2 described in production process 2.

Production Process 19

The compound (1-2) described in production process 1 may be produced, for example, by the following process:

wherein m1, R⁶ and R⁵¹ are as defined above.

1) Step 1

A compound (19-2) may be produced from a compound (19-1) by the same production process as described in literature (for example, J. Org. Chem. 58, 879 (1993)).

2) Step 2

The compound (1-2) may be produced from the compound (19-2) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.

Production Process 20

The compound (1-3) described in production process 1 may be produced, for example, by the following process:

wherein m1, R⁶ and R⁵¹ are as defined above, and R⁸⁰ is an alkyl group.

1) Step 1

A compound (20-2) may be produced by reacting a compound (20-1) with thionyl chloride in an alcohol solvent. The alcohol solvent includes methanol, ethanol, etc. The amount of thionyl chloride used is usually chosen in the range of 2 to 10 equivalents per equivalent of the compound (20-1). The reaction temperature may be chosen in the range of about −90° C. to about 30° C.

2) Step 2

A compound (20-3) may be produced by reacting the compound (20-2) with a base in water solvent. The base includes sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc. The reaction temperature may be chosen in the range of about 30° C. to about 100° C.

3) Step 3

A compound (20-4) may be produced from the compound (20-3) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.

4) Step 4

The compound (1-3) may be produced by reacting the compound (20-4) with a reducing agent in an inert solvent. The reducing agent includes aluminum lithium hydride, borane complexes (e.g. borane-dimethyl sulfide complexes and borane-tetrahydrofuran complexes) and the like. The inert solvent includes tetrahydrofuran, 1,4-dioxane, mixed solvents thereof, and the like. The reaction temperature is chosen in the range of about −20° C. to about 60° C.

Examples of the synthesis of compounds (1-2a) to (1-2j) as specific examples of the compound (1-2) are given below. The compounds (1-2a) to (1-2j) include pharmaceutically acceptable salts thereof.

[Formula 53] Production Compound process

WO 02/48138J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

J. Org. Chem. 44, 2732 (1979)J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

[Formula 54] Production Compound process

(1-2g) Synthesized from compound (1-2f) asa starting material according to, forexample, the process described inJ. Org. Chem. 44, 3872 (1979),J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-2h): X⁴ = CH₃(1-2i): X⁴ = CH₂CH₃(1-2j): X⁴ = CH₂CH₂CH₃ Arch. Pharm. 322, 499 (1989)J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.) wherein R⁵¹ is as defined above.

As hydrochloride of the compound (1-2e), a commercial one may also be used. It is also possible to synthesize the compound (1-2) from a substituted DL-ornithine by a well-known process. A specific example of the process is that described in literature (for example, R. C. Ralock, “Comprehensive Organic transformation”, VCH publisher Inc., 1989).

Examples of the synthesis of compounds (1-3a) to (1-31) as specific examples of the compound (1-3) are given below. The compounds (1-3a) to (1-31) include pharmaceutically acceptable salts thereof.

[Formula 55] Compound Production process

(1-3a) WO 01/27082J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3b) Int. J. Peptide Protein Res. 40, 119 (1992)WO 1/27082J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3c) US 4413141WO 01/27082J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3d) Tetrahedron: Asymmetry 8, 327 (1997)WO 01/27082J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3e) Tetrahedron: Asymmetry 11, 567 (2000)J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.) wherein R⁵¹ is as defined above.

[Formula 56] Compound Production process

(1-3f) Chem. Eur. J. 6, 2830 (2000)WO 00/26332J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3g) JP-T-2002-525325J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3h) Bull. Chem. Soc. Jpn. 53, 2605 (1980)J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3i) Synthesized from compound (1-3h) asa starting material according to, forexample, the process described inJ. Am. Chem. Soc. 80, 2584 (1958),J. Chem. Soc. PT1 499 (1972), J. Chem. Soc.,Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.) wherein R⁵¹ is as defined above, and Y¹⁰ is NH₂, Alloc, NHBoc or NHCbz.

Examples of the synthesis of compounds (1-3j) to (1-3v) as specific examples of the compound (1-3) are given below. The compounds (1-3j) to (1-3v) include pharmaceutically acceptable salts thereof.

[Formula 57] Compound Production process

(1-3j) Synthesized from compound (1-3f in which Y¹⁰ isNH₂) as a starting material according to, forexample, the process described inJ. Chem. Soc. Chem. Commun. 611 (1981),J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3k) Synthesized from compound (1-3f in which Y¹⁰ isNH₂) as a starting material according to, forexample, the process described inJ. Chem. Soc. Chem. Commun. 611 (1981),J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3l) Synthesized from compound (1-3h) as a startingmaterial according to, for example, the processdescribed inJ. Org. Chem. 44, 3872 (1979),J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3m) Synthesized from compound (1-3e) as a startingmaterial according to, for example, the processdescribed inJ. Org. Chem. 44, 3872 (1979),J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3n) Synthesized from compound (1-3h) as a startingmaterial according to, for example, the processdescribed inBull. Chem. Soc. Jpn. 64, 2857 (1991),J. Chem. Soc., Perkin Trans. 1, 2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.) wherein R⁵¹ is as defined above.

[Formula 58] Compound Production process

(1-3o) Synthesized from compound (1-3f inwhich Y¹⁰ is NH₂) as a starting materialaccording to, for example, the processdescribed in Tetrahedron Lett. 40, 5609(1999), J. Chem. Soc., Perkin Trans. 1,2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3p): Y¹² = (R)—C₆H₅(1-3q): Y¹² = (S)—C₆H₅ J. Med. Chem. 35, 833 (1992), R. C.Larock, “Comprehensive Organictransformation”, VCH publisher Inc.,1989, J. Chem. Soc., Perkin Trans. 1,2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3r): Y¹³ = NHS(O)₂CH₃(1-3s): Y¹³ = NHC(O)CH₃(1-3t): Y¹³ = NHC(O)C₆H₅(1-3u): Y¹³ = N(CH₃)C(O)CH₃ Synthesized from compound (1-3f inwhich Y¹⁰ is NH₂) as a starting materialaccording to, for example, the processdescribed in R. C. Larock“Comprehensive Organictransformation”, VCH publisher Inc., 1989, J. Chem. Soc., Perkin Trans. 1,2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.)

(1-3v) WO 02/068420J. Chem. Soc., Perkin Trans. 1, 2233(1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.) wherein R⁵¹ is as defined above.

Examples of the synthesis of compounds (1-3w) to (1-3dd) as specific examples of the compound (1-3) are given below. The compounds (1-3w) to (1-3dd) include pharmaceutically acceptable salts thereof.

[Formula 59] Compound Production process

(1-3w): Y¹⁴ = 2-CH₃—C₆H₅(1-3x): Y¹⁴ = 3-CH₃—C₆H₅(1-3y): Y¹⁴ = 4-CH₃—C₆H₅(1-3z): Y¹⁴ = 2-CH₃O—C₆H₅(1-3aa): Y¹⁴ = 3-CH₃O—C₆H₅(1-3bb): Y¹⁴ = 4-CH₃O—C₆H₅(1-3cc): Y¹⁴ = C₆H₅ (1-3dd): Y¹⁴ = CH₂C₆H₅ Synthesized from compound (1-3f inwhich Y¹⁰ is NH₂) as a starting materialaccording to, for example, the processdescribed in R. C. Larock,“Comprehensive Organictransformation”, VCH publisher Inc.,1989, J. Org.. Chem. 66, 3593 (2001),J. Prakt. Chem. 342, 421 (2000),Tetrahedron Lett. 36, 5611 (1994),J. Org.. Chem. 53, 5143 (1988), Bioorg. Med. Chem. Lett. 11, 1281(2001), J. Chem. Soc., Perkin Trans. 1,2233 (1999)Protective Groups in Organic Synthesis2nd Edition (John Wiley & Sons, Inc.) wherein R⁵¹ is as defined above.

The compound (1-3) may be synthesized from a substituted D-ornithine by a well-known process. A specific example of the process is that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

Production Process 21

The compound (1-5) described in production process 1 may be produced, for example, by the following process:

wherein m2, R⁷ and R⁵¹ are as defined above.

1) Step 1

A compound (21-2) may be produced from a compound (21-1) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.

2) Steps 2 to 4

The compound (1-5) may be produced from the compound (21-2) by the same process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

Examples of the synthesis of compounds (1-5a) to (1-5aa) as specific examples of the compound (1-5) are given below. The compounds (1-5a) to (1-5aa) include pharmaceutically acceptable salts thereof.

The compounds (1-5a) to (1-5aa) may be produced according to the processes described in literature (for example, WO01/74774 and R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

wherein R⁵¹ is as defined above.

Examples of the synthesis of compounds (1-5bb) to (1-5tt) as specific examples of the compound (1-5) are given below. The compounds (1-5bb) to (1-5tt) include pharmaceutically acceptable salts thereof.

The compounds (1-5bb) to (1-5tt) may be produced according to the processes described in literature (for example, WO01/74774, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, and Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).

wherein R⁵¹ is as defined above.

Production Process 22

A compound (22-10) as a specific example of the compound (1-6) described in production process 1 may be produced, for example, by the following process:

wherein R¹⁰⁰, R¹⁰¹ and R¹⁰² are independently a hydrogen atom, “an optionally substituted alkyl group”, “an optionally substituted aryl group” or “an optionally substituted aralkyl group”, and R⁹⁹ is a hydrogen atom or methoxy.

1) Step 1

A compound (22-3) may be produced by carrying out reductive amination of a compound (22-1) with a compound (22-2) by the same method as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989). 2) Steps 2 to 4

A compound (22-7) may be produced from the compound (22-3) by the same production process as described in literature (e.g. WO01/07436).

3) Step 5

A compound (22-8) may be produced from the compound (22-7) by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).

4) Step 6

A compound (22-9) may be produced from the compound (22-8) by the same production process as described in literature (for example, J. Chem. Soc. Perkin Trans. 13281 (2001), Heterocycles 38, 17 (1994), Tetrahedron Lett. 34, 6673 (1993), J. Org. Chem. 60, 4602 (1995) and J. Med. Chem. 38, 2866 (1995)).

5) Step 7

The compound (22-10) may be produced from the compound (22-9) by the same process as that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989) or the like.

Examples of the synthesis of compounds (22-10a) to (22-101) as specific examples of the compound (22-10) are given below. The compounds (22-10a) to (22-101) include pharmaceutically acceptable salts thereof.

Production Process 23

Each of compounds of the formula (23-2), formula (23-3), formula (23-5), formula (23-6), formula (23-7), formula (23-8) and formula (12-1) is produced, for example, by the following process:

wherein A¹, A², R¹, R² and Y¹ are as defined above; R⁶⁷O is “an optionally substituted alkoxy group”; and each of M² and M³ is lithium, sodium or potassium.

1) Step 1

The compound (23-2) may be produced from a compound (23-1) by the same production process as described in literature (for example, Can. J. Chem. 78, 697 (2000)).

2) Step 2

The compound (23-3) may be produced by reacting the compound (23-2) with 2,5-dimethoxytetrahydrofuran in the presence of thionyl chloride and in the presence or absence of an inert solvent. The amount of thionyl chloride used is usually chosen in the range of 0.1 to 3 equivalents per equivalent of the compound (23-2). The amount of 2,5-dimethoxytetrahydrofuran used is usually chosen in the range of 10 to 100 equivalents per equivalent of the compound (23-2), and 2,5-dimethoxytetrahydrofuran may be used also as a solvent. The inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), aprotic solvents (e.g. acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide), and mixed solvents thereof. Suitable examples thereof are N,N-dimethylformamide and dimethyl sulfoxide. The reaction temperature may be chosen in the range of about 10° C. to about 80° C.

3) Step 3

The compound (23-5) may be produced by reacting the compound (23-3) with a compound (23-4) in an inert solvent. The amount of the compound (23-4) used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (23-3). The inert solvent includes alcohol solvents (e.g. methanol, ethanol and 2-propanol) and the like. The reaction temperature may be chosen in the range of about 30° C. to about 100° C.

4) Step 4

The compound (23-6) may be produced by reacting the compound (23-5) with a base in an inert solvent. As the base, alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide) are exemplified, and an aqueous solution of the base may be used. The amount of the base used is usually chosen in the range of 1 to 30 equivalents per equivalent of the compound (23-5). The inert solvent includes alcohol solvents (e.g. methanol, ethanol and 2-propanol), water, mixed solvents thereof, and the like. The reaction temperature may be chosen in the range of about 30° C. to about 130° C.

5) Step 5

The compound (23-7) may be produced from the compound (23-5) by the same process as in the step 2 described in production process 2.

6) Step 6

The compound (23-8) may be produced from the compound (23-7) by the same process as in the above step 4.

7) Step 7

The compound (12-1) may be produced by reacting the compound (23-6) in an inert solvent in the presence or absence of an organic acid. The organic acid includes, for example, acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid and ascorbic acid. The inert solvent includes, for example, alcohol solvents (e.g. methanol, ethanol and 2-propanol), ether solvents (e.g. tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), aprotic solvents (e.g. acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide), and mixed solvents thereof. The reaction temperature may be chosen in the range of about 0° C. to about 100° C.

Production Process 24

Each of compounds of the formula (24-3), formula (24-6) and formula (24-8) as the compound of the formula (I), or a salt thereof and a compound of the formula (13-1) are produced, for example, by the following processes:

wherein A¹, A², R¹, R², Y¹ and Y are as defined above; C(O)NR⁶⁸R⁶⁹ is “an optionally substituted carbamoyl group”; and R⁷⁰ is “an optionally substituted alkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted alkynyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted aralkyl group” or “an optionally substituted heteroarylalkyl group”.

1) Step 1

A compound (24-2) may be produced from a compound (23-6) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 972-976 (1989)).

2) Step 2, Step 6 and Step 8 By the same process as in the step 2 described in production process 2, the compound (24-3) may be produced from the compound (24-2), the compound (24-6) from a compound (24-5), and the compound (24-8) from a compound (24-7).

3) Step 3

A compound (24-4) may be produced from a compound (23-6) by the same production process as described in literature (for example, Bioorg. Med. Chem. Lett. 11, 2951 (2001), Tetrahedron Letters 42, 8955 (2001), Organic Letters 2, 4091 (2000), Synlett 5, 715 (2002), Bioorg. Med. Chem. Lett. 11, 287 (2001), Tetrahedron Letters 45, 7107 (2004) and Tetrahedron Letters 42, 3763 (2001)).

4) Step 4

The compound (13-1) may be produced from the compound (24-4) by the same production process as described in literature (for example, Tetrahedron Letters 45, 7107 (2004)).

5) Step 5

The compound (24-5) may be produced from the compound (13-1) by the same production process as described in literature (for example, Indian J. Chem. 33B, 1103 (1994)).

6) Step 6 and Step 8

The compound (24-6) may be produced from the compound (24-5) by the same process as in the step 2 described in production process 2.

7) Step 7

The compound (24-7) may be produced from the compound (24-5) by the same process as that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989) or the like.

Production Process 25

A compound of the formula (25-1) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein R², R²⁹, Y and Y¹ are as defined above.

1) Step 1

The compound (25-1) may be produced from a compound (1-13) by the same process as in the step 2 described in production process 2.

Production Process 26

Each of compounds of the formula (26-2), formula (26-4), formula (26-6) and formula (26-8) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:

wherein A¹, A², R¹, R², Y¹ and Y are as defined above, and R⁷¹ is an alkyl group.

1) Step 1 and Step 3

A compound (26-3) may be produced from a compound (12-1) by the same production process as described in literature (for example, J. Am. Chem. Soc. 74, 3916 (1952)).

2) Step 2

The compound (26-2) may be produced from a compound (26-1) by the same process as in the step 2 described in production process 2.

3) Step 4

The compound (26-4) may be produced from the compound (26-3) by the same process as in the step 2 described in production process 2.

4) Step 5 and Step 7

A compound (26-7) may be produced from a compound (26-1) by the same production process as described in literature (for example, J. Org. Chem. 22, 355 (1957)).

6) Step 6

The compound (26-6) may be produced from a compound (26-5) by the same process as in the step 2 described in production process 2.

7) Step 8

The compound (26-8) may be produced from the compound (26-7) by the same process as in the step 2 described in production process 2.

Production Process 27

A compound of the formula (27-2) as the compound of the formula (23-1) described in production process 23 is produced, for example, by the following process:

wherein R¹, R², R²⁹ and Y¹ are as defined above.

1) Step 1

A compound (27-1) may be produced from a compound (1-13) by the same production process as described in literature (for example, Tetrahedron 50, 3259 (1994)).

2) Step 2

The compound (27-2) may be produced from the compound (27-1) by the same production process as described in literature (for example, Tetrahedron 50, 3259 (1994)).

Unless otherwise specified, the starting materials, reagents and the like used above may be commercial compounds or may be produced from well-known compounds by well-known processes.

In each of the production processes described above, when the starting compound in each reaction has a reactive group such as hydroxyl group, amino group or carboxyl group, the reactive group in a site other than a site where the reaction is desired is previously protected with a suitable protective group if necessary, and the protective group is removed after carrying out each reaction or after carrying out several reactions, whereby a desired compound may be obtained. As the protective group for protecting the hydroxyl group, amino group, carboxyl group or the like, conventional protective groups used in the field of organic synthetic chemistry may be used. The introduction and removal of such a protective group may be carried out according to a conventional method (for example, the method described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).

For example, the protective group for the hydroxyl group includes tert-butyldimethylsilyl group, methoxymethyl group, tetrahydropyranyl group and the like. The protective group for the amino group includes tert-butoxycarbonyl group, benzyloxycarbonyl group and the like. Such a protective group for the hydroxyl group may be removed by reaction in a solvent such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid. In the case of tert-butyldimethylsilyl group, it is also possible to carry out the removal in a solvent such as tetrahydrofuran in the presence of, for example, tetrabutylammonium fluoride. When the protective group for the amino group is tert-butoxycarbonyl group, it may be removed, for example, by reaction in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid. In the case of benzyloxycarbonyl group, the removal may be carried out, for example, by reaction in a solvent such as acetic acid in the presence of an acid such as hydrobromic acid.

As a form in which the carboxyl group is protected, tert-butyl esters, orthoesters and acid amides are exemplified. The protective group used for this protection is removed as follows. In the case of the tert-butyl esters, the removal is carried out, for example, by reaction in an aqueous solvent in the presence of hydrochloric acid. In the case of the orthoesters, the removal is carried out, for example, by treatment with an acid and then an alkali such as sodium hydroxide in a solvent such as aqueous methanol, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane. In the case of the acid amides, the removal may be carried out, for example, by reaction in a solvent such as water, aqueous methanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid or sulfuric acid.

The compound of the formula (I) includes those having a center for optical activity. Such a compound having a center for optical activity may be obtained as a racemic modification, or it may be obtained as an optically active substance when an optically active starting material is used. If necessary, the racemic modification obtained may be physically or chemically resolved into optical antipodes by a well-known method. Preferably, diastereomers are formed from the racemic modification by a reaction using a reagent for optical resolution. The diastereomers different in form may be resolved by a well-known method such as fractional crystallization.

The compound or prodrug thereof of the present invention may be converted to a salt, for example, by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol or acetone. The pharmaceutically acceptable acid includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.

The present inventive compounds are expected to be usable for the treatment of various diseases because of their inhibitory effect on DPP-IV. The compounds described in the present description are useful for the suppression of postprandial hyperglycemia in prediabetes, the treatment of non-insulin-dependent diabetes, the treatment of autoimmune diseases such as arthritis and articular rheumatism, the treatment of intestinal mucosa diseases, growth acceleration, the inhibition of transplantation rejection, the treatment of obesity, the treatment of eating disorder, the treatment of HIV infection, the suppression of cancer metastasis, the treatment of prostatomegaly, the treatment of periodontitis, and the treatment of osteoporosis.

When used for the treatment, the present inventive compounds may be administered as a pharmaceutical composition orally or parenterally (for example, by intravenous, subcutaneous or intramuscular injection, locally, intrarectally, percutaneously, or through nose). Compositions for the oral administration include, for example, tablets, capsules, pills, granules, powders, solutions and suspensions. Compositions for the parenteral administration include, for example, aqueous or oily preparations for injection, ointments, creams, lotions, aerosols, suppositories and patches. These pharmaceutical compositions are prepared by conventional techniques and may contain non-toxic and inactive carriers or excipients conventionally used in the field of formulation.

Although the dose is varied depending on the individual compounds, the disease, age, body weight and sex of a patient, symptom, administration route and the like, the bicyclic pyrrole derivative of the present invention, the prodrug thereof or the pharmaceutically acceptable salt of the derivative or prodrug is administered to an adult (body weight: 50 kg) usually in a dose of 0.1 to 1000 mg/day, preferably 1 to 300 mg/day in one portion or two or three portions a day. It is also possible to administer the derivative, prodrug or salt at intervals of several days to several weeks.

The present inventive compounds may be used in combination with drugs such as remedies for diabetes, remedies for diabetic complications, hypolipidemic drugs, hypotensors, antiobesity drugs, diuretics, etc. (these drugs are hereinafter abbreviated as concomitant drugs) in order to enhance the effects of the compounds. The timing of administration of the present inventive compound and the concomitant drug(s) is not limited. They may be administered to an object of administration either at the same time or at different times. It is also possible to prepare a mixture of the present inventive compound and the concomitant drug(s). The dose of the concomitant drug(s) may be properly chosen on the basis of a dose clinically employed. The proportions of the present inventive compound and the concomitant drug(s) may be properly chosen depending on an object of administration, an administration route, a disease to be treated, symptoms, a combination of the compound and the concomitant drug(s), and the like. For example, when the object of administration is a human being, the concomitant drug(s) is used in an amount of 0.01 to 100 parts by weight per part by weight of the present inventive compound.

The remedies for diabetes include insulin products (e.g. animal insulin products extracted from bovine or porcine pancreas; and human insulin products synthesized by a genetic engineering technique by the use of Escherichia coli or yeast), insulin resistance improving agents (e.g. pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297 and CS-011), α-glucosidase inhibitors (e.g. voglibose, acarbose, miglitol and emiglitate), biguanide preparations (e.g. metformin), insulin secretion accelerators (e.g. sulfonylurea preparations such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.; repaglinide, senaglinide, nateglinide and mitiglinide), GLP-1, GLP-1 analogs (e.g. exenatide, liraglutide, SUN-E7001, AVEO10, BIM-51077 and CJC1131), protein tyrosine phosphatase inhibitors (e.g. vanadates), and β3 agonists (e.g. GW-427353B and N-5984).

The remedies for diabetic complications includes aldose reductase inhibitors (e.g. tolrestat, epalresat, zenarestat, zopolrestat, minarestat, fidarestat, SK-860 and CT-112), neurotrophic factors (e.g. NGF, NT-3 and BDNF), PKC inhibitors (e.g. LY-333531), AGE inhibitors (e.g. ALT946, pimagedine, pyratoxathine and N-phenacylthiazolium bromide (ALT766)), active-oxygen removers (e.g. thioctic acid), and cerebrovasodilators (e.g. tiapride and mexiletine). The hypolipidemic drugs include HMG-CoA reductase inhibitors (e.g. pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, and their sodium salts), squalene synthetase inhibitors, ACAT inhibitors, and the like. The hypotensors include angiotensin-converting-enzyme inhibitors (e.g. captopril, enalapril, aracepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril and trandolapril), angiotensin II antagonists (e.g. ormesartan, medoxomill, candesartan, cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan and tasosartan), calcium antagonists (e.g. nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine and amlodipine), and the like.

The antiobesity drugs include, for example, central antiobesity drugs (e.g. phentermine, sibutramine, amfepramone, dexamfetamine, mazindol and SR-141716A), pancreas lipase inhibitors (e.g. orlistat), peptidergic anorexiants (e.g. leptin and CNTF (ciliary nerve trophic factor)) and cholecystokinin agonists (e.g. lintitript and FPL-15849). The diuretics include, for example, xanthine derivatives (e.g. sodium salicylate theobromine and calcium salicylate theobromine), thiazide preparations (e.g. ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, polythiazide and methyclothiazide), anti-aldosterone preparations (e.g. spironolactone and triamterene), carbonate dehydratase inhibitors (e.g. acetazolamide), chlorobenzenesulfoneamide preparations (e.g. chlorthalidone, mefruside and indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide and furosemide.

The concomitant drugs are preferably GLP-1, the GLP-1 analogs, the α-glucosidase inhibitors, the biguanide preparations, the insulin secretion accelerators, the insulin resistance improving agents, and the like. The above-exemplified concomitant drugs may be used in combination of two or more thereof in proper proportions.

When the present inventive compound is used in combination with the concomitant drug(s), the amount of the drug(s) used may be reduced so as to be within a safe range in view of the side effects of the drug(s). In particular, the dose of the biguanide preparations may be reduced as compared with a conventional dose. Therefore, side effects causable by these drugs are safely preventable. In addition, the doses of the remedies for diabetic complications, the hypolipidemic drugs, the hypotensors and the like may be reduced. As a result, side effects causable by these drugs are effectively preventable.

EXAMPLES

The present invention is more concretely illustrated below with reference examples, working examples and test examples, which should not be construed as limiting the scope of the invention. The nomenclature of compounds shown in the reference examples and working examples mentioned below is not always based on IUPAC. Abbreviations are used in these examples for the simplification of description in some cases and they have the same meanings as defined above.

Example 1 Example 1 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chlorobenzyl)-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

A 4N hydrochloric acid/1,4-dioxane solution (5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate (185 mg) in 1,4-dioxane (3 ml), and the resulting mixture was stirred at 25° C. for 2 hours and then concentrated under reduced pressure to obtain the title compound (170 mg).

¹H NMR (400 MHz, CD₃OD) δ 7.48-7.41 (m, 1H), 7.36-7.16 (m, 3H), 6.91-6.78 (m, 3H), 6.57-6.49 (m, 1H), 5.69 (s, 2H), 4.06 (q, J=7.0 Hz, 2H), 3.73-3.60 (m, 2H), 3.50 (s, 3H), 3.49-3.42 (m, 1H), 3.10-2.92 (m, 2H), 2.10-1.98 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.45 (m, 2H), 1.40 (t, J=7.0 Hz, 3H).

MS (ESI+) 533 (M⁺+1, 100%).

Example 2 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

The title compound was synthesized from a corresponding compound by the same process as in Example 1.

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.44 (m, 1H), 7.30-7.16 (m, 2H), 6.65-6.58 (m, 1H), 5.72-5.62 (m, 2H), 3.73 (s, 3H), 3.70-3.61 (m, 1H), 3.51-3.41 (m, 1H), 3.27 (s, 3H), 3.23-3.10 (m, 1H), 3.05-2.97 (m, 2H), 2.13-2.03 (m, 1H), 1.82-1.72 (m, 1H), 1.63-1.41 (m, 2H).

MS (ESI+) 427 (M⁺+1, 88%).

Example 3 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chlorobenzyl)-2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

The title compound was synthesized from a corresponding compound by the same process as in Example 1.

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.44 (m, 1H), 7.32-7.20 (m, 2H), 6.65-6.60 (m, 1H), 5.67-5.57 (m, 2H), 3.52-3.45 (m, 1H), 3.27-3.15 (m, 2H), 3.26 (s, 3H), 3.09-2.94 (m, 2H), 2.12-2.04 (m, 1H), 1.83-1.75 (m, 1H), 1.66-1.43 (m, 2H).

MS (ESI+) 413 (M⁺+1, 93%).

Example 4 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chlorobenzyl)-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

The title compound was synthesized from a corresponding compound by the same process as in Example 1.

¹H NMR (400 MHz, CD₃OD) δ 7.49-7.44 (m, 1H), 7.31-7.17 (m, 2H), 6.63-6.57 (m, 1H), 5.78-5.63 (m, 2H), 3.81 (s, 3H), 3.79-3.68 (m, 1H), 3.58 (s, 3H), 3.37-3.17 (m, 2H), 3.15-3.05 (m, 1H), 3.03-2.92 (m, 1H), 2.15-2.03 (m, 1H), 1.84-1.76 (m, 1H), 1.67-1.43 (m, 2H).

MS (ESI+) 475 (M⁺+1, 100%).

Example 5 6-(3-Aminopiperidin-1-yl)-5-(2-chlorobenzyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione hydrochloride

The title compound was synthesized from a corresponding compound by the same process as in Example 1.

¹H NMR (400 MHz, CD₃OD) δ 7.43-7.40 (m, 1H), 7.25-7.11 (m, 2H), 6.47-6.42 (m, 1H), 6.04 (s, 1H), 5.66-5.53 (m, 2H), 3.48 (s, 3H), 3.38-3.28 (m, 2H), 3.25 (s, 3H), 2.95-2.85 (m, 2H), 2.81-2.71 (m, 1H), 2.07-1.98 (m, 1H), 1.84-1.73 (m, 1H), 1.67-1.49 (m, 2H).

MS (ESI+) 402 (M⁺+1, 100%).

Example 6 6-(3-Aminopiperidin-1-yl)-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione hydrochloride

The title compound was synthesized from a corresponding compound by the same process as in Example 1.

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.43 (m, 1H), 7.04-6.98 (m, 1H), 6.17-6.14 (m, 1H), 6.05 (s, 1H), 5.56 (s, 2H), 3.49 (s, 3H), 3.40-3.21 (m, 2H), 3.27 (s, 3H), 2.97-2.70 (m, 3H), 2.08-1.98 (m, 1H), 1.86-1.73 (m, 1H), 1.68-1.46 (m, 2H).

MS (ESI+) 420 (M⁺+1, 100%).

Example 7 2-{[6-(3-Aminopiperidin-1-yl)-5-(2-chlorobenzyl)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl]oxy}benzamide hydrochloride

The title compound was synthesized from a corresponding compound by the same process as in Example 1.

¹H NMR (400 MHz, CD₃OD) δ 8.04-7.97 (m, 1H), 7.50-7.41 (m, 2H), 7.32-7.17 (m, 2H), 7.00-6.91 (m, 2H), 6.67-6.59 (m, 1H), 5.71 (s, 2H), 3.57 (s, 3H), 3.72-3.20 (m, 3H), 3.15-2.97 (m, 2H), 2.15-2.03 (m, 1H), 1.87-1.75 (m, 1H), 1.70-1.42 (m, 2H).

MS (ESI+) 532 (M⁺+1, 100%).

Each of the compounds of Examples 8 to 70 was synthesized according to the processes described in a corresponding reference example and Example 1.

[Formula 77]

Example No. R² Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 8

¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (brs, 3H), 7.86 (d, J=6.6 Hz, 1H), 7.57 (m, 1H), 7.43 (t, J=7.6 Hz, 1H) 6.62 (d, J=7.9 Hz, 1H), 6.12 (s, 1H), 5.64 (d, J=16.2 Hz, 1H), 5.56 (d, J=16.2 Hz, 1H), 3.39 (s, 3H), 3.36-3.23 (m, 2H), 3.11 (s, 3H), 2.92-2.75 (m, 3H), 1.91-1.80 (m, 2H), 1.55-1.51 (m, 2H).

MS (ESI+) 393 (M⁺+1, 100%).

Example 9

¹H NMR (400 MHz, CD₃OD) δ 7.10-7.03 (m, 1H), 6.28-6.25 (m, 1H), 6.02 (s, 1H), 5.58 (s, 2H), 3.47 (s, 3H), 3.41-2.79 (m, 5H), 3.27 (s, 3H), 2.10-1.52 (m, 4H).

MS (ESI+) 422 (M⁺+1, 100%).

Example 10

¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (brs, 3H), 7.23-7.18 (m, 1H), 6.95-6.90 (m, 1H), 6.05 (s, 1H), 5.98-5.94 (m, 1H), 5.40 (d, J=16.5 Hz, 1H), 5.32 (d, J=16.5 Hz, 1H), 3.38 (s, 3H), 3.35-3.23 (m, 2H), 3.11 (s, 3H), 2.86-2.81 (m, 2H), 2.68-2.64 (m, 1H), 2.32 (s, 3H), 1.88-1.74 (m, 2H), 1.49-1.44 (m, 2H).

MS (ESI+) 400 (M⁺+1, 100%).

Example 11

¹H NMR (300 MHz, CD₃OD) δ 7.09-6.88 (m, 3H), 6.19 (d, J=7.5 Hz, 1H), 5.93 (s, 1H), 5.43 (d, J=16.3 Hz, 1H), 5.36 (d, J=16.3 Hz, 1H), 3.38 (s, 3H), 3.27-3.21 (m, 2H), 3.14 (s, 3H), 2.89-2.73 (m, 3H), 2.31 (s, 3H), 1.94-1.91 (m, 1H), 1.70-1.49 (m, 3H).

MS (ESI+) 382 (M⁺+1, 100%).

Example 12

¹H NMR (300 MHz, CDCl₃) δ 7.64-7.59 (m, 1H), 6.83-6.79 (m, 1H), 6.32 (d, J=2.4 Hz, 1H), 5.67 (s, 1H), 5.66 (s, 1H), 5.60 (s, 1H), 3.74 (s, 3H), 3.47 (s, 3H), 3.36 (s, 3H), 3.03-2.93 (m, 2H), 2.86-2.82 (m, 1H), 2.69-2.61 (m, 1H), 2.52-2.46 (m, 1H), 1.88-1.61 (m, 4H).

MS (ESI+) 423 (M⁺+1, 100%).

Example 13

¹H NMR (300 MHz, CDCl₃) δ 8.50 (brs, 3H), 7.71-7.65 (m, 1H), 7.07-7.00 (m, 1H), 6.57-6.53 (m, 1H), 5.84 (d, J=16.7 Hz, 1H), 5.73 (s, 1H), 5.64 (d, J=16.7 Hz, 1H), 3.59-3.57 (m, 1H), 3.45 (s, 3H), 3.39-3.37 (m, 1H), 3.33 (s, 3H), 3.16-3.09 (m, 1H), 2.70-2.68 (m, 2H), 2.08-2.06 (m, 1H), 1.80-1.78 (m, 2H), 1.60-1.58 (m, 1H).

MS (ESI+) 411 (M⁺+1, 100%).

Example 14

¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (brs, 3H), 5.91 (s, 1H), 5.08-4.89 (m, 2H), 3.35 (s, 3H), 3.35-3.28 (m, 2H), 3.21 (s, 3H), 2.99-2.89 (m, 3H), 1.95-1.91 (m, 2H), 1.76 (s, 3H), 1.67-1.63 (m, 2H).

MS (ESI+) 330 (M⁺+1, 100%).

Example 15

¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (brs, 3H), 7.53-7.49 (m, 1H), 7.32-7.24 (m, 2H), 6.41-6.38 (m, 1H), 6.05 (s, 1H), 5.63 (s, 2H), 3.37 (s, 3H), 3.30-3.19 (m, 2H), 3.14 (s, 3H), 2.82-2.78 (m, 2H), 2.62-2.60 (m, 1H), 1.91-1.87 (m, 1H), 1.71-1.69 (m, 1H), 1.47-1.45 (m, 2H).

MS (ESI+) 411 (M⁺+1, 100%).

[Formula 78]

Example No. R¹ R² Example16

Example17 CH₃

Example18

Example19 PhC(O)CH₂

Example20 H

Example 16

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.43 (m, 1H), 7.22-7.19 (m, 2H), 7.04-7.01 (m, 1H), 6.79-6.75 (m, 2H), 6.18-6.15 (m, 1H), 6.03 (s, 1H), 5.56 (s, 2H), 5.01 (s, 2H), 3.73 (s, 3H), 3.47 (s, 3H), 3.40-2.73 (m, 5H), 2.12-1.52 (m, 4H).

MS (ESI+) 526 (M⁺+1, 100%).

Example 17

¹H NMR (400 MHz, CD₃OD) δ 7.49-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.18-7.15 (m, 1H), 7.08-7.03 (m, 1H), 5.91 (s, 1H), 3.50 (s, 3H), 3.40-3.30 (m, 1H), 3.12 (s, 3H), 3.11-3.00 (m, 2H), 2.80-2.66 (m, 2H), 2.01-1.92 (m, 1H), 1.68-1.59 (m, 1H), 1.50-1.30 (m, 2H).

MS (ESI+) 384 (M⁺+1, 100%)

Example 18

¹H NMR (400 MHz, CD₃OD) δ 8.58-8.56 (m, 1H), 8.36-8.33 (m, 1H), 8.25-8.17 (m, 2H), 8.12-8.07 (m, 1H), 7.90-7.84 (m, 1H), 7.46-7.42 (m, 1H), 7.05-6.99 (m, 1H), 6.27-6.23 (m, 1H), 6.13 (s, 1H), 5.93 (s, 2H), 5.56 (s, 2H), 3.50 (s, 3H), 3.40-3.30 (m, 2H), 3.01-2.92 (m, 2H), 2.89-2.77 (m, 1H), 2.10-2.03 (m, 1H), 1.92-1.81 (m, 1H), 1.75-1.53 (m, 2H).

MS (ESI+) 547 (M⁺+1, 100%).

Example 19

¹H NMR (400 MHz, CD₃OD) δ 8.04-8.01 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.50 (m, 2H), 7.44-7.40 (m, 1H), 7.03-6.98 (m, 1H), 6.24-6.20 (m, 1H), 6.11 (s, 1H), 5.56 (s, 2H), 5.39 (s, 2H), 3.51 (s, 3H), 3.40-3.30 (m, 2H), 3.00-2.91 (m, 2H), 2.85-2.79 (m, 1H), 2.10-2.02 (m, 1H), 1.90-1.80 (m, 1H), 1.72-1.53 (m, 2H).

MS (ESI+) 524 (M⁺+1, 100%).

Example 20

¹H NMR (400 MHz, CD₃OD) δ 7.48-7.44 (m, 1H), 7.06-7.01 (m, 1H), 6.22-6.19 (m, 1H), 6.07 (s, 1H), 5.55 (s, 2H), 3.45 (s, 3H), 3.40-3.28 (m, 2H), 3.00-2.92 (m, 2H), 2.85-2.77 (m, 1H), 2.11-2.01 (m, 1H), 1.90-1.81 (m, 1H), 1.82-1.53 (m, 2H).

MS (ESI+) 406 (M⁺+1, 100%).

[Formula 79]

Example No. R³ Example 21 C(O)NH₂ Example 22

Example 23 C(O)OCH₃ Example 24 C(O)OCH₂CH₃ Example 25 C(O)N(CH₃)₂ Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 21

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.43 (m, 1H), 7.30-7.17 (m, 2H), 6.49-6.44 (m, 1H), 5.69 (s, 2H), 3.57 (s, 3H), 3.30 (s, 3H), 3.18-2.90 (m, 5H), 2.08-1.99 (m, 1H), 1.77-1.68 (m, 1H), 1.55-1.35 (m, 2H).

MS (ESI+) 445 (M⁺+1, 59%).

Example 22

¹H NMR (400 MHz, CD₃OD) δ 7.49-7.42 (m, 1H), 7.30-7.21 (m, 2H), 6.58-6.54 (m, 1H), 5.76 (s, 2H), 3.29 (s, 3H), 3.10-2.75 (m, 3H), 3.05 (s, 3H), 2.53-2.32 (m, 2H), 1.98-1.85 (m, 1H), 1.62-1.49 (m, 1H), 1.40-1.16 (m, 2H)

MS (ESI+) 470 (M⁺+1, 100%).

Example 23

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.43 (m, 1H), 7.29-7.21 (m, 2H), 6.47-6.43 (m, 1H), 5.75 (s, 2H), 3.94 (s, 3H), 3.54 (s, 3H), 3.32 (s, 3H), 3.10-2.81 (m, 4H), 2.72-2.62 (m, 1H), 1.96-1.89 (m, 1H), 1.61-1.54 (m, 1H), 1.40-1.25 (m, 2H).

MS (ESI+) 460 (M⁺+1, 100%).

Example 24

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.44 (m, 1H), 7.29-7.17 (m, 2H), 6.47-6.43 (m, 1H), 5.79-5.69 (m, 2H), 4.43-4.34 (m, 2H), 3.56 (s, 3H), 3.35 (s, 3H), 3.17-2.72 (m, 5H), 2.07-1.97 (m, 1H), 1.72-1.63 (m, 1H), 1.48-1.30 (m, 2H), 1.43-1.38 (m, 3H).

MS (ESI+) 474 (M⁺+1, 100%).

Example 25

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.44 (m, 1H), 7.30-7.20 (m, 2H), 6.56-6.52 (m, 1H), 5.72-5.68 (m, 2H), 3.42 (s, 3H), 3.27 (s, 3H), 3.27-3.20 (m, 1H), 3.16-3.11 (m, 6H), 2.95-2.85 (m, 3H), 2.08-1.99 (m, 1H), 1.76-1.68 (m, 1H), 1.50-1.30 (m, 3H).

MS (ESI+) 473 (M⁺+1, 100%).

Example 26

¹H NMR (400 MHz, CD₃OD) δ 7.46-7.43 (m, 1H), 7.30-7.20 (m, 2H), 6.55-6.50 (m, 1H), 5.79-5.60 (m, 2H), 3.91-3.62 (m, 8H), 3.40 (s, 3H), 3.27 (s, 3H), 3.27-3.10 (m, 1H), 2.97-2.75 (m, 3H), 2.05-1.95 (m, 1H), 1.78-1.63 (m, 1H), 1.54-1.25 (m, 3H).

MS (ESI+) 515 (M⁺+1, 100%).

Example 27

¹H NMR (400 MHz, CD₃OD) δ 7.46-7.43 (m, 1H), 7.29-7.20 (m, 2H), 6.53-6.48 (m, 1H), 5.69 (s, 2H), 3.71-3.59 (m, 4H), 3.50-2.78 (m, 5H), 3.44 (s, 3H), 3.34-3.26 (m, 3H), 2.09-1.93 (m, 5H), 1.78-1.68 (m, 1H), 1.65-1.38 (m, 2H)

MS (ESI+) 499 (M⁺+1, 100%).

Example 28

¹H NMR (400 MHz, CD₃OD) δ 7.39-7.34 (m, 1H), 7.22-7.11 (m, 2H), 6.50-6.43 (m, 1H), 5.67-5.52 (m, 2H), 4.48-3.80 (m, 4H), 3.55-3.47 (m, 3H), 3.35 (s, 3H), 3.30-3.10 (m, 2H), 2.85-2.11 (m, 5H), 1.69-1.41 (m, 4H).

MS (ESI+) 485 (M⁺+1, 100%).

Example 29

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.36 (m, 1H), 7.21-7.10 (m, 2H), 6.46-6.42 (m, 1H), 5.69 (d, J=17 Hz, 1H), 5.61 (d, J=17 Hz, 1H), 3.58 (s, 3H), 3.35 (s, 3H), 3.32-3.27 (m, 2H), 3.08-3.03 (m, 1H), 2.91-2.83 (m, 2H), 2.78-2.60 (m, 2H), 1.85-1.16 (m, 4H), 1.10-1.02 (m, 1H), 0.61-0.56 (m, 2H), 0.31-0.27 (m, 2H).

MS (ESI+) 499 (M⁺+1, 100%).

Example 30

¹H NMR (400 MHz, CDCl₃) δ 8.46 (brs, 3H), 7.37-7.33 (m, 1H), 7.25-7.10 (m, 2H), 6.60 (brs, 1H), 6.52-6.42 (m, 1H), 5.72-5.50 (m, 2H), 3.56-3.42 (m, 1H), 3.49 (s, 3H), 3.40-3.13 (m, 4H), 3.32 (s, 3H), 2.88-2.72 (m, 2H), 2.12-1.98 (m, 1H), 1.96-0.99 (m, 15H).

MS (ESI+) 541 (M⁺+1, 100%).

Example 31

¹H NMR (400 MHz, CDCl₃) δ 8.70-8.33 (brs, 3H), 7.38-7.34 (m, 1H), 7.22-7.10 (m, 2H), 6.91-6.77 (brs, 1H), 6.43-6.36 (m, 1H), 5.74 (d, J=16 Hz, 1H), 5.50 (d, J=16 Hz, 1H), 4.51 (m, 1H), 3.49 (s, 3H), 3.32 (s, 3H), 3.28-3.18 (m, 2H), 2.83-2.74 (m, 2H), 2.53-2.30 (m, 2H), 2.09-1.90 (m, 3H), 1.81-1.60 (m, 6H).

MS (ESI+) 499 (M⁺+1, 100%).

Example 32

MS (ESI+) 519 (M⁺+1, 100%).

Example 33

¹H NMR (400 MHz, CDCl₃) δ 8.43 (brs, 3H), 7.39-7.33 (m, 1H), 7.23-7.13 (m, 2H), 6.60-6.53 (m, 1H), 5.74-5.52 (m, 2H), 4.47-2.53 (m, 11H), 3.50-3.31 (m, 6H), 2.20-1.22 (m, 8H).

MS (ESI+) 529 (M⁺+1, 100%).

Example 34

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.35 (m, 1H), 7.21-7.13 (m, 2H), 6.50-6.45 (m, 1H), 5.78-5.52 (m, 2H), 4.27-4.15 (m, 1H), 3.98-3.14 (m, 7H), 3.53-3.49 (m, 3H), 3.35-3.33 (m, 3H), 2.94-2.82 (m, 1H), 2.75-2.65 (m, 1H), 2.13-1.38 (m, 8H).

MS (ESI+) 529 (M⁺+1, 100%).

Example 35

¹H NMR (400 MHz, CD₃OD) δ 7.51-7.45 (m, 1H), 7.31-7.18 (m, 2H), 7.03 (q, J=5.4 Hz, 1H), 6.53-6.45 (m, 1H), 5.81-5.65 (m, 2H), 4.69-4.56 (m, 1H), 3.57 (s, 3H), 3.32 (s, 3H), 3.21-2.67 (m, 5H), 2.13-1.82 (m, 3H), 1.80-1.69 (m, 1H), 1.67 (d, J=5.4 Hz, 3H), 1.66-1.22 (m, 10H).

MS (ESI+) 616 (M⁺+1, 45%).

[Formula 80]

Example No. R³ Example 36 C(O)N(CH₃)₂ Example 37 C(O)NHCH₃ Example 38

Example 39

Example 40

Example 41

Example 42

Example 43

Example 44

Example 36

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m, 1H), 7.00-6.90 (m, 1H), 6.32-6.25 (m, 1H), 5.63-5.50 (m, 2H), 3.53-3.28 (m, 3H), 3.45-3.33 (m, 6H), 3.28-3.03 (m, 6H), 2.82-2.65 (m, 2H), 2.21-2.10 (m, 1H), 1.81-1.40 (m, 3H).

MS (ESI+) 491 (M⁺+1, 100%).

Example 37

¹H NMR (400 MHz, CDCl₃) δ 8.50 (brs, 3H), 7.37-7.31 (m, 1H), 6.95-6.85 (m, 2H), 6.25-6.18 (m, 1H), 5.62 (d, J=17 Hz, 1H), 5.46 (d, J=17 Hz, 1H), 3.58-3.40 (m, 1H), 3.47 (s, 3H), 3.38-3.20 (m, 2H), 3.32 (s, 3H), 3.01 (s, 3H), 2.82-2.72 (m, 2H), 2.20-1.41 (m, 4H).

MS (ESI+) 477 (M⁺+1, 100%).

Example 38

¹H NMR (400 MHz, CDCl₃) δ 8.59 (brs, 3H), 7.38-7.31 (m, 1H), 7.02 (brs, 1H), 6.93-6.87 (m, 1H), 6.25-6.13 (m, 1H), 5.63 (d, J=17 Hz, 1H), 5.44 (d, J=17 Hz, 1H), 3.61-3.53 (m, 1H), 3.45 (s, 3H), 3.31 (s, 3H), 3.38-3.20 (m, 2H), 3.03-2.95 (m, 1H), 2.83-2.73 (m, 2H), 2.23-1.62 (m, 4H), 0.93-0.83 (m, 2H), 0.74-0.58 (m, 2H).

MS (ESI+) 503 (M⁺+1, 100%).

Example 39

¹H NMR (400 MHz, CDCl₃) δ 8.52 (brs, 3H), 7.41-7.35 (m, 1H), 7.00-6.89 (m, 1H), 6.78 (brs, 1H), 6.30-6.16 (m, 1H), 5.78-5.62 (m, 1H), 5.49-5.38 (m, 1H), 3.59-3.21 (m, 5H), 3.52 (s, 3H), 3.33 (s, 3H), 2.88-2.71 (m, 2H), 2.21-1.45 (m, 4H), 1.16-1.04 (m, 1H), 0.65-0.49 (m, 2H), 0.38-0.25 (m, 2H).

MS (ESI+) 517 (M⁺+1, 100%).

Example 40

¹H NMR (400 MHz, CDCl₃) δ 8.60 (brs, 3H), 7.41-7.30 (m, 1H), 6.96-6.83 (m, 1H), 6.77 (brs, 1H), 6.28-6.10 (m, 1H), 5.75-5.33 (m, 2H), 4.59-4.42 (m, 1H), 3.49 (s, 3H), 3.40-3.19 (m, 2H), 3.33 (s, 3H), 2.84-2.66 (m, 2H), 2.54-2.33 (m, 2H), 2.22-1.91 (m, 3H), 1.87-1.50 (m, 6H)

MS (ESI+) 517 (M⁺+1, 100%).

Example 41

¹H NMR (400 MHz, CDCl₃) δ 8.50 (brs, 3H), 7.37-7.33 (m, 1H), 6.93-6.89 (m, 2H), 6.30-6.23 (m, 1H), 5.64 (d, J=17 Hz, 1H), 5.45 (d, J=17 Hz, 1H), 3.79-3.58 (m, 4H), 3.55-3.22 (m, 3H), 3.51 (s, 3H), 3.36 (s, 3H), 3.34 (s, 3H), 2.89-2.69 (m, 2H), 2.18-1.43 (m, 4H).

MS (ESI+) 521 (M⁺+1, 100%).

Example 42

¹H NMR (400 MHz, CDCl₃) δ 8.57 (brs, 3H), 7.51 (brs, 1H), 7.41-7.29 (m, 1H), 6.95-6.83 (m, 1H), 6.21-6.11 (m, 1H), 5.67 (d, J=17 Hz, 1H), 5.44 (d, J=17 Hz, 1H), 4.31-3.97 (m, 2H), 3.51-3.12 (m, 3H), 3.45 (s, 3H), 3.29 (s, 3H), 2.82-2.69 (m, 2H), 2.11-1.35 (m, 4H).

MS (ESI+) 545 (M⁺+1, 100%).

Example 43

¹H NMR (400 MHz, CD₃OD) δ 7.49-7.44 (m, 1H), 7.08-7.00 (m, 1H), 6.29-6.24 (m, 1H), 5.64 (d, J=17 Hz, 1H), 5.58 (d, J=17 Hz, 1H), 3.57 (s, 3H), 3.30 (s, 3H), 2.30-1.25 (m, 23H).

MS (ESI+) 613 (M⁺+1, 100%).

Example 44

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.33 (m, 1H), 6.97-6.89 (m, 1H), 6.33-6.24 (m, 1H), 5.72-5.49 (m, 2H), 4.00-3.62 (m, 8H), 3.50-3.34 (m, 6H), 3.45-2.62 (m, 5H), 2.19-1.49 (m, 4H).

MS (ESI+) 533 (M⁺+1, 100%).

[Formula 81]

Examole No. R¹² R² R³ Example 45 CH₃

Example 46 CH₃

Example 47 CH₃

Example 48 CH₃

Example 49 CH₃

Example 50 CH₃

Example 51 CH₃

Example 52 CH₃

Example 45

¹H NMR (300 MHz, DMSO-d₆) δ 8.79 (d, J=4.0 Hz, 1H), 8.04 (brs, 3H), 7.88 (d, J=7.5 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 6.62 (d, J=7.5 Hz, 1H), 5.69 (d, J=16.3 Hz, 1H), 5.59 (d, J=16.3 Hz, 1H), 3.36 (s, 3H), 3.24-3.19 (m, 1H), 3.15 (s, 3H), 2.94-2.73 (m, 4H), 1.92-1.90 (m, 1H), 1.70-1.67 (m, 1H), 1.46-1.23 (m, 3H), 0.74-0.68 (m, 2H), 0.58-0.53 (m, 2H).

MS (ESI+) 476 (M⁺+1, 100%).

Example 46

¹H NMR (300 MHz, DMSO-d₆) δ 8.96 (d, J=7.5 Hz, 1H), 7.99 (brs, 3H), 7.90-7.87 (m, 1H), 7.61 (m, 1H), 7.45 (t, J=7.4 Hz, 1H), 6.62 (d, J=7.7 Hz, 1H), 5.70 (d, J=16.5 Hz, 1H), 5.59 (d, J=16.5 Hz, 1H), 4.39-4.31 (m, 1H), 3.37 (s, 3H), 3.26-3.19 (m, 1H), 3.15 (s, 3H), 2.92-2.83 (m, 3H), 2.26-2.23 (m, 2H), 2.03-1.87 (m, 3H), 1.74-1.62 (m, 3H), 1.42-1.23 (m, 3H).

MS (ESI+) 490 (M⁺+1, 100%).

Example 47

¹H NMR (400 MHz, CD₃OD) δ 7.76-7.73 (m, 1H), 7.57-7.52 (m, 1H), 7.44-7.38 (m, 1H), 6.76-6.72 (m, 1H), 5.81 (d, J=17 Hz, 1H), 5.73 (d, J=17 Hz, 1H), 3.60-3.53 (m, 4H), 3.53 (s, 3H), 3.38 (s, 3H), 3.28 (s, 3H), 3.14-3.11 (m, 1H), 2.92-2.85 (m, 2H), 2.76-2.68 (m, 2H), 1.99-1.84 (m, 1H), 1.78-1.59 (m, 1H), 1.51-1.13 (m, 2H).

MS (ESI+) 494 (M⁺+1, 100%).

Example 48

¹H NMR (400 MHz, CD₃OD) δ 5.16-5.01 (m, 2H), 3.47-3.41 (m, 2H), 3.44 (s, 3H), 3.34 (s, 3H), 3.29-3.22 (m, 1H), 3.12-3.03 (m, 2H), 2.94-2.87 (m, 1H), 2.17-1.77 (m, 3H), 1.77-1.73 (m, 3H), 1.64-1.50 (m, 1H), 0.87-0.79 (m, 2H), 0.64-0.58 (m, 2H).

MS (ESI+) 413 (M⁺+1, 100%).

Example 49

¹H NMR (400 MHz, CD₃OD) δ 5.15-5.02 (m, 2H), 3.60-3.52 (m, 4H), 3.48-3.06 (m, 5H), 3.47 (s, 3H), 3.37 (s, 3H), 3.34 (s, 3H), 2.14-2.05 (m, 1H), 1.96-1.78 (m, 3H), 1.76-1.73 (m, 3H), 1.66-1.55 (m, 1H).

MS (ESI+) 431 (M⁺+1, 100%).

Example 50

¹H NMR (400 MHz, CD₃OD) δ 7.80-7.75 (m, 1H), 7.60-7.53 (m, 1H), 7.47-7.41 (m, 1H), 6.83-6.78 (m, 1H), 5.87 (d, J=17 Hz, 1H), 5.73 (d, J=17 Hz, 1H), 4.21-4.07 (m, 2H), 3.47 (s, 3H), 3.30 (s, 3H), 3.25-2.76 (m, 5H), 2.11-1.98 (m, 1H), 1.78-1.35 (m, 3H).

MS (ESI+) 518 (M⁺+1, 100%).

Example 51

¹H NMR (400 MHz, CD₃OD) δ 7.90-7.86 (m, 1H), 7.26-7.19 (m, 1H), 6.59-6.55 (m, 1H), 5.84 (d, J=17 Hz, 1H), 5.73 (d, J=17 Hz, 1H), 3.65-3.55 (m, 4H), 3.53 (s, 3H), 3.41 (s, 3H), 3.37 (s, 3H), 3.14-2.76 (m, 5H), 2.11-2.01 (m, 1H), 1.81-1.71 (m, 1H), 1.61-1.38 (m, 2H).

MS (ESI+) 512 (M⁺+1, 100%).

Example 52

¹H NMR (400 MHz, CD₃OD) δ 7.92-7.85 (m, 1H), 7.27-7.20 (m, 1H), 6.60-6.53 (m, 1H), 5.87 (d, J=17 Hz, 1H), 5.74 (d, J=17 Hz, 1H), 4.23-4.10 (m, 2H), 3.49 (s, 3H), 3.40-2.82 (m, 5H), 3.30 (s, 3H), 2.12-2.02 (m, 1H), 1.71-1.37 (m, 3H).

MS (ESI+) 536 (M⁺+1, 100%).

[Formula 82]

Example No. R² Example 53

Example 54

Example 53

¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (bs, 3H), 7.51-7.48 (m, 1H), 7.32-7.21 (m, 2H), 6.43 (d, J=6.8 Hz, 1H), 5.63 (d, J=16.6 Hz, 1H), 5.55 (d, J=16.6 Hz, 1H), 3.66 (s, 3H), 3.36-3.16 (m, 2H), 3.16 (s, 3H), 2.96-2.72 (m, 3H), 1.92-1.90 (m, 1H), 1.62-1.60 (m, 1H), 1.25-1.22 (m, 2H).

MS (ESI+) 436 (M⁺+1, 100%).

Example 54

¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (bs, 3H), 7.87 (d, J=6.8 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 6.78-6.76 (m, 1H), 5.74 (d, J=16.4 Hz, 1H), 5.63 (d, J=16.4 Hz, 1H), 3.64 (s, 3H), 3.22-3.18 (m, 2H), 3.15 (s, 3H), 3.01-2.95 (m, 2H), 2.68-2.66 (m, 1H), 1.96-1.92 (m, 1H), 1.63-1.61 (m, 1H), 1.41-1.32 (m, 2H).

MS (ESI+) 427 (M⁺+1, 100%).

[Formula 83]

Example No. R³ Salt Example 55

2 HCl Example 56 CH₂OCH₃ HCl Example 57 Br CF₃CO₂H Example 58 F CF₃CO₂H Example 59 CH₃ HCl Example 60 CHO CF₃CO₂H Example 61 CH₃C(O) CF₃CO₂H Example 62

CF₃CO₂H

Example 55

¹H NMR (300 MHz, DMSO-d₆) δ 10.01-9.87 (m, 1H), 8.35-8.17 (m, 3H), 7.51 (d, J=7.7 Hz, 1H), 7.32-7.18 (m, 2H), 6.34-6.21 (m, 1H), 5.65-5.56 (m, 2H), 4.42-4.26 (m, 2H), 3.67 (s, 3H), 3.55-3.36 (m, 2H), 3.15 (s, 3H), 2.91-2.60 (m, 3H), 2.79 (s, 6H), 2.01-1.49 (m, 4H).

MS (ESI+) 458 (M⁺+1, 56%).

Example 56

¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (brs, 3H), 7.49 (d, J=7.5 Hz, 1H), 7.31-7.22 (m, 2H), 6.31-6.28 (m, 1H), 5.63-5.53 (m, 2H), 4.55-4.51 (m, 2H), 3.70 (s, 3H), 3.65 (s, 3H), 3.50-3.47 (m, 1H), 3.17 (s, 3H), 3.08-3.05 (m, 1H), 2.79-2.75 (m, 3H), 1.94-1.91 (m, 1H), 1.56-1.35 (m, 3H).

MS (ESI+) 446 (M⁺+1, 10%).

Example 57

¹H NMR (300 MHz, CDCl₃) δ 9.25 (brs, 3H), 7.44-7.36 (m, 1H), 7.18-7.04 (m, 2H), 6.44-6.39 (m, 1H), 5.68 (s, 2H), 3.83 (s, 3H), 3.46-3.60 (m, 1H), 3.37 (s, 3H), 3.22-3.04 (m, 3H), 2.70-2.64 (m, 1H), 2.12-1.94 (m, 1H), 1.68-1.42 (m, 3H).

MS (ESI+) 482 (M⁺+1, 48%).

Example 58

¹H NMR (300 MHz, CDCl₃) δ 7.40-7.37 (m, 1H), 7.20-7.16 (m, 2H), 6.51-6.48 (m, 1H), 5.79 (d, J=16.5 Hz, 1H), 5.57 (d, J=16.5 Hz, 1H), 3.62 (s, 3H), 3.46-3.44 (m, 1H), 3.37 (s, 3H), 3.34-3.32 (m, 1H), 3.14-3.09 (m, 1H), 2.87-2.85 (m, 2H), 1.86-1.62 (m, 4H).

MS (ESI+) 420 (M⁺+1, 61%).

Example 59

¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (brs, 3H), 7.50-7.47 (m, 1H), 7.29-7.19 (m, 2H), 6.30-6.28 (m, 1H), 5.58 (d, J=16.1 Hz, 1H), 5.49 (d, J=16.1 Hz, 1H), 3.61 (s, 3H), 3.16 (s, 3H), 3.07-3.04 (m, 2H), 2.91-2.65 (m, 3H), 2.31 (s, 3H), 1.93-1.90 (m, 1H), 1.57-1.54 (m, 1H), 1.25-1.15 (m, 2H).

MS (ESI+) 416 (M⁺+1, 100%).

Example 60

¹H NMR (300 MHz, CDCl₃) δ 10.12 (s, 1H), 7.51 (brs, 3H), 7.38-7.35 (m, 1H), 7.24-7.11 (m, 2H), 6.44 (d, J=6.2 Hz, 1H), 5.73-5.69 (m, 2H), 3.79 (s, 3H), 3.49-3.44 (m, 1H), 3.39 (s, 3H), 3.23-3.20 (m, 1H), 3.03-2.78 (m, 3H), 1.90-1.55 (m, 4H).

MS (ESI+) 430 (M⁺+1, 85%).

Example 61

¹H NMR (300 MHz, CDCl₃) δ 7.91 (brs, 3H), 7.39-7.36 (m, 1H), 7.21-7.13 (m, 2H), 6.38 (d, J=7.5 Hz, 1H), 5.70 (s, 2H), 3.44 (s, 3H), 3.37 (s, 3H), 3.31-3.27 (m, 1H), 3.20-3.17 (m, 2H), 3.06-2.94 (m, 2H), 2.53 (s, 3H), 2.15-1.85 (m, 2H), 1.65-1.54 (m, 2H).

MS (ESI+) 444 (M⁺+1, 100%).

Example 62

¹H NMR (300 MHz, CDCl₃) δ 7.38-7.36 (m, 1H), 7.26-7.19 (m, 4H), 6.96-6.89 (m, 2H), 6.52-6.49 (m, 1H), 6.66-5.52 (m, 2H), 3.84 (s, 3H), 3.39 (s, 3H), 3.19-3.15 (m, 1H), 3.09 (s, 3H), 3.04-2.46 (m, 4H), 1.80-1.40 (m, 4H).

MS (ESI+) 508 (M⁺+1, 100%).

[Formula 84]

Example No. R² R³ Example 63

CN Example 64

H Example 65

C(O)N(CH₃)₂ Example 66

Example 63

¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.31 (brs, 3H), 7.50 (d, J=6.6 Hz, 1H), 7.33-7.21 (m, 2H), 6.49 (d, J=6.6 Hz, 1H), 5.64 (d, J=17.0 Hz, 1H), 5.56 (d, J=17.0 Hz, 1H), 3.56-3.54 (m, 1H), 3.42 (s, 3H), 3.26-3.19 (m, 1H), 3.08-2.87 (m, 3H), 1.96-1.93 (m, 1H), 1.75-1.72 (m, 1H), 1.52-1.43 (m, 2H).

MS (ESI+) 397 (M⁺+1, 100%).

Example 64

¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.21 (brs, 3H), 7.58-7.53 (m, 1H), 7.20-7.13 (m, 1H), 6.19 (s, 1H), 6.05-6.01 (m, 1H), 5.60 (d, J=16.8 Hz, 1H), 5.52 (d, J=16.8 Hz, 1H), 3.42 (s, 3H), 3.31-3.16 (m, 2H), 2.91-2.84 (m, 2H), 2.73-2.67 (m, 1H), 1.92-1.79 (m, 2H), 1.55-1.47 (m, 2H).

MS (ESI+) 390 (M⁺+1, 100%).

Example 65

¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (brs, 4H), 7.57-7.52 (m, 1H), 7.19-7.12 (m, 1H), 6.14-6.09 (m, 1H), 5.60 (d, J=17.0 Hz, 1H), 5.53 (d, J=17.0 Hz, 1H), 3.42 (s, 3H), 3.23-3.21 (m, 1H), 3.01 (s, 3H), 3.00 (s, 3H), 2.96-2.94 (m, 2H), 2.79-2.76 (m, 2H), 1.90-1.88 (m, 1H), 1.70-1.67 (m, 1H), 1.35-1.30 (m, 2H).

MS (ESI+) 461 (M⁺+1, 100%).

Example 66

¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.19 (brs, 3H), 7.58-7.53 (m, 1H), 7.20-7.13 (m, 1H), 6.19-6.15 (m, 1H), 5.56 (s, 2H), 3.69-3.55 (m, 6H), 3.48-3.41 (m, 2H), 3.41 (s, 3H), 3.22-3.17 (m, 1H), 3.00-2.96 (m, 2H), 2.81-2.79 (m, 2H), 1.90-1.88 (m, 1H), 1.69-1.67 (m, 1H), 1.35-1.33 (m, 2H).

MS (ESI+) 503 (M⁺+1, 100%).

[Formula 85]

Example No. R¹³ Example 67 SO₂Me Example 68 C(O)NH₂ Example 69 CN

Example 67

¹H NMR (300 MHz, DMSO-d₆) δ 8.02 (brs, 3H), 7.61-7.56 (m, 1H), 7.24-7.18 (m, 1H), 6.65-6.61 (m, 1H), 5.55 (s, 2H), 3.69 (s, 3H), 3.64 (s, 3H), 3.53-3.50 (m, 1H), 3.27-3.17 (m, 2H), 3.08-3.03 (m, 1H), 2.96-2.93 (m, 1H), 1.97-1.95 (m, 1H), 1.78-1.75 (m, 1H), 1.49-1.45 (m, 2H).

MS (ESI+) 493 (M⁺+1, 100%).

Example 68

¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.21 (s, 1H), 7.99 (brs, 3H), 7.61-7.56 (m, 1H), 7.25-7.17 (m, 1H), 6.48-6.44 (m, 1H), 5.54 (s, 2H), 3.54-3.51 (m, 1H), 3.42 (s, 3H), 3.27-3.21 (m, 2H), 3.11-3.07 (m, 1H), 2.97-2.94 (m, 1H), 1.97-1.95 (m, 1H), 1.79-1.77 (m, 1H), 1.51-1.47 (m, 2H).

MS (ESI+) 458 (M⁺+1, 100%).

Example 69

¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (brs, 3H), 7.61-7.55 (m, 1H), 7.24-7.17 (m, 1H), 6.54-6.50 (m, 1H), 5.54 (s, 2H), 3.59 (s, 3H), 3.55-3.53 (m, 1H), 3.29-3.22 (m, 2H), 3.12-3.08 (m, 1H), 2.95-2.93 (m, 1H), 1.96-1.94 (m, 1H), 1.79-1.77 (m, 1H), 1.49-1.47 (m, 2H).

MS (ESI+) 440 (M⁺+1, 100%).

Example 70 6-[(3S)-3-Aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

MS (ESI+) 445 (M⁺+1, 100%).

Example 71 Sodium 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

A 1N aqueous sodium hydroxide solution (1 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) were added to methyl 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate hydrochloride (53 mg), and the resulting mixture was stirred at 80° C. for 3 hours. After the reaction solution was cooled to 25° C., water was added thereto, followed by washing with ethyl acetate, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (41 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.41-7.38 (m, 1H), 7.22-7.13 (m, 2H), 6.42-6.38 (m, 1H), 5.67 (d, J=17 Hz, 1H), 5.58 (d, J=17 Hz, 1H), 3.65 (s, 3H), 3.27 (s, 3H), 3.20-3.13 (m, 1H), 3.05-2.95 (m, 1H), 2.93-2.85 (m, 1H), 2.83-2.75 (m, 1H), 2.64-2.54 (m, 1H), 1.83-1.73 (m, 1H), 1.64-1.52 (m, 1H), 1.40-1.25 (m, 2H).

MS (ESI+) 445 (M⁺+1, 100%).

The compound of Example 72 was synthesized from a corresponding compound according to the process described in Example 1.

Example 72 Ethyl 3-amino-5-[(3R)-3-aminopiperidin-1-yl]-1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate hydrochloride

MS (ESI+) 402 (M⁺+1, 100%).

Example 73 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H, 5H)dione trifluoroacetate

Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (54 g) in chloroform (1 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (45 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.27 (s, 1H), 7.90 (brs, 3H), 7.49-7.45 (m, 1H), 7.28-7.18 (m, 2H), 6.29-6.26 (m, 1H), 5.48 (s, 2H), 3.60 (s, 3H), 3.18-3.08 (m, 2H), 3.14 (s, 3H), 2.98-2.72 (m, 3H), 1.87-1.85 (m, 1H), 1.66-1.64 (m, 1H), 1.33-1.31 (m, 2H).

MS (ESI+) 418 (M⁺+1, 100%).

Example 74 Methyl 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-7-cyano-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-carboxylate

Methyl cyanoformate (170 μl) was added to a solution of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (104 mg) in hydrochloric acid-methanol reagent 10 (4 ml), and the resulting mixture was stirred with heating at 90° C. in a sealed tube for 15 hours. The reaction solution was concentrated under reduced pressure and chloroform was added to the residue. The solid precipitated was removed by filtration and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether, and the solid precipitated was collected by filtration to obtain a crude product of the title compound (107 mg).

MS (ESI+) 459 (M⁺+1, 13%). Each of the compounds of Examples 75 and 76 was synthesized from a corresponding compound according to the process described in Example 1.

Example 75 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chlorobenzyl)-7-methoxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione trifluoroacetate

¹H NMR (300 MHz, CDCl₃) δ ppm 7.40-7.37 (m, 1H), 7.22-7.12 (m, 2H), 6.39-6.36 (m, 1H), 5.84 (d, J=17.4 Hz, 1H), 5.49 (d, J=17.4 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.42-3.33 (m, 2H), 3.37 (s, 3H), 3.13-3.10 (m, 1H), 2.96-2.88 (m, 2H), 1.87-1.64 (m, 4H).

MS (ESI+) 432 (M⁺+1, 100%).

Example 76 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile

¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (brs, 3H), 7.57-7.53 (m, 1H), 7.21-7.14 (m, 1H), 6.39-6.34 (m, 1H), 5.54 (d, J=17.4 Hz, 1H), 5.48 (d, J=17.4 Hz, 1H), 3.47-3.44 (m, 1H), 3.40 (s, 3H), 3.25-3.15 (m, 2H), 3.05-3.01 (m, 1H), 2.94-2.87 (m, 1H), 2.53 (s, 3H), 1.94-1.92 (m, 1H), 1.79-1.77 (m, 1H), 1.52-1.48 (m, 2H).

MS (ESI+) 429 (M⁺+1, 100%).

Reference Example 1 tert-Butyl {(3R)-1-[2,2-d]cyano-1-(methylthio)vinyl]piperidin-3-yl}carbamate

A solution of [bis(methylthio)methylene]-propanedinitrile (10 g) and (R)-tert-3-butyl piperidin-3-ylcarbamate (11.8 g) in ethanol (350 ml) was stirred at 80° C. for 3 hours, and the reaction solution was cooled to 25° C. and then concentrated under reduced pressure to obtain the title compound (19 g) as a light-yellow amorphous substance.

¹H NMR (400 MHz, CDCl₃) δ ppm 4.60-4.48 (m, 1H), 4.18-4.03 (m, 1H), 3.94-3.80 (m, 1H), 3.77-3.61 (m, 1H), 3.59-3.35 (m, 2H), 2.61 (s, 3H), 2.12-2.00 (m, 1H), 1.98-1.86 (m, 1H), 1.82-1.68 (m, 1H), 1.68-1.50 (m, 1H), 1.46 (s, 9H).

MS (ESI+) 323 (M⁺+1, 40%).

Reference Example 2 Ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chlorobenzy)-4-cyano-1H-pyrrole-2-carboxylate

2-Chlorobenzylamine (1.7 ml) was added to a solution of tert-butyl {(3R)-1-[2,2-d]cyano-1-(methylthio)vinyl]piperidin-3-yl}carbamate (15 g) in isopropanol (28 ml), and the resulting mixture was heated under reflux. After 5 hours, 2-chlorobenzylamine (2.8 ml) was added thereto, followed by heating under reflux for another 10 hours. The reaction solution was cooled to 25° C. and then concentrated under reduced pressure, and the resulting residue was roughly purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1). The reaction mixture (9.82 g) thus obtained was dissolved in acetone (90 ml), followed by adding thereto potassium carbonate (6.2 g) and ethyl bromoacetate (1.5 ml), and the resulting mixture was stirred at 60° C. for 3 hours. The reaction solution was cooled to 25° C. and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue (7.53 g) was dissolved in tetrahydrofuran (150 ml) and the resulting solution was cooled to 0° C. Then, sodium hydride (60%, 780 mg) was added thereto and the resulting mixture was stirred for 1 hour while being slowly warmed to 25° C. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/1) to obtain the title compound (2.7 g) as a white amorphous substance.

MS (ESI+) 502 (M⁺+1, 100%).

Reference Example 3 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylthio)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Under a nitrogen atmosphere, methyl isothiocyanate (71 μl) and potassium carbonate (143 mg) were added to a solution (2.5 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (260 mg) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 3 hours. After the reaction solution was cooled to 25° C. and then concentrated under reduced pressure, toluene (5 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. To the resulting residue was added acetone (2.5 ml), and the resulting mixture was cooled to 0° C. Methyl iodide (65 μl) was added dropwise thereto and the resulting mixture was warmed to 25° C. and stirred for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (250 mg).

¹H NMR (400 MHz, CDCl₃) δ 7.41-7.36 (m, 1H), 7.23-7.08 (m, 2H), 6.49-6.40 (m, 1H), 5.71 (d, J=17.0 Hz, 1H), 5.61 (d, J=17.0 Hz, 1H), 3.80-3.69 (m, 1H), 3.52 (s, 3H), 3.50-3.42 (m, 1H), 3.04-2.91 (m, 3H), 2.68 (s, 3H), 1.88-1.76 (m, 1H), 1.74-1.50 (m, 3H), 1.42 (s, 9H).

MS (ESI+) 543 (M⁺+1, 100%).

Reference Example 4 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Sodium tungstate dihydrate (139 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylthio)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (230 mg) in a mixture of methanol (2 ml), acetic acid (0.7 ml) and water (0.25 ml), and the resulting mixture was heated to 5° C. A 30% aqueous hydrogen peroxide solution (0.29 ml) was added dropwise thereto, followed by stirring at 60° C. for 4 hours. After the reaction mixture was allowed to cool, the precipitate formed was collected by filtration, washed with water and then dried under reduced pressure to obtain the title compound (230 mg) as a white solid.

MS (ESI+) 575 (M⁺+1, 46%).

Reference Example 5 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (100 mg) in ethanol (1 ml) was added 1N sodium hydroxide (1 ml), and the resulting mixture was stirred at 80° C. for 5 hours. After the reaction solution was allowed to cool, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (81 mg) as a white solid.

MS (ESI+) 513 (M⁺+1, 40%).

Reference Example 6 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Potassium carbonate (700 mg) and methyl iodide (0.34 ml) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.3 g) in N,N-dimethylformamide, and the resulting mixture was stirred at 25° C. for 4 hours. After the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (1.1 g) as a white solid.

¹H NMR (400 MHz, CDC1) δ 7.42-7.38 (m, 1H), 7.25-7.13 (m, 2H), 6.56-6.48 (m, 1H), 5.69 (d, J=16.5 Hz, 1H), 5.59 (d, J=16.5 Hz, 1H), 3.76 (s, 3H), 3.75-3.65 (m, 1H), 3.50-3.41 (m, 1H), 3.35 (s, 3H), 3.01-2.84 (m, 3H), 1.89-1.78 (m, 1H), 1.69-1.45 (m, 3H), 1.42 (s, 9H)

MS (ESI+) 527 (M⁺+1, 100%).

Reference Example 7 N-(1-{(3R)-3-[(tert-Butoxycarbonyl)amino]-piperidin-1-yl}-2,2-dicyanovinyl)glycine ethyl ester

Glycine methyl ester hydrochloride (3.3 g) and triethylamine (3.7 ml) were added to a solution of tert-butyl {(3R)-1-[2,2-d]cyano-1-(methylthio)vinyl]-piperidin-3-yl}carbamate (1.3 g) in ethanol (30 ml), and the resulting mixture was heated under reflux. After 4 hours, triethylamine (1.5 ml) was added thereto, followed by heating under reflux for another 7 hours. After the reaction solution was cooled to 25° C., a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (360 mg) as a white amorphous substance.

¹H NMR (400 MHz, CDCl₃) δ 5.76 (brs, 1H), 4.58 (brd, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.15 (dd, J=1.0, 5.2 Hz, 2H), 3.84-3.79 (m, 1H), 3.69-3.58 (m, 2H), 3.40-3.30 (m, 1H), 3.28-3.18 (m, 1H), 2.05-1.95 (m, 1H), 1.89-1.79 (m, 1H), 1.74-1.63 (m, 1H), 1.60-1.49 (m, 1H), 1.45 (s, 9H) 1.32 (t, J=7.1 Hz, 3H).

MS (ESI+) 378 (M⁺+1, 10%).

Reference Example 8 N-(1-{(3R)-3-[(tert-Butoxycarbonyl)amino]-piperidin-1-yl}-2,2-dicyanovinyl)-N-(2-chlorobenzyl)glycine ethyl ester

A solution of N-(1-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)glycine ethyl ester (300 mg), 2-chlorobenzyl bromide (0.15 ml) and potassium carbonate (330 mg) in acetone (4 ml) was stirred at 25° C. for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (340 mg) as a white amorphous substance.

MS (ESI+) 502 (M⁺+1, 25%).

Reference Example 9 Ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate

A solution of N-(1-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)-N-(2-chlorobenzyl)glycine ethyl ester (320 mg) in tetrahydrofuran (5 ml) was cooled to 0° C., followed by adding thereto sodium hydride (33 mg), and the resulting mixture was stirred for 1 hour while being warmed to 25° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (300 mg).

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.35 (m, 1H), 7.21-7.09 (m, 2H), 6.57-6.49 (m, 1H), 5.47-5.30 (m, 2H), 4.07 (q, J=7.0 Hz, 2H), 3.76-3.64 (m, 1H), 3.40-3.30 (m, 1H), 3.00-2.82 (m, 3H), 1.87-1.74 (m, 1H), 1.72-1.46 (m, 3H), 1.41 (s, 9H), 1.07 (t, J=7.0 Hz, 3H).

MS (ESI+) 502 (M⁺+1, 29%).

Reference Example 10 tert-Butyl [(3R)-1-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)piperidin-3-yl]carbamate

Under ice-cooling, water (2 ml) and concentrated sulfuric acid (4 ml) were added to tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (300 mg), and the resulting mixture was stirred at 140° C. After 3 hours, the reaction solution was cooled to 0° C. and adjusted to pH 8 or higher by dropwise addition of a 5N aqueous potassium carbonate solution. The reaction solution was extracted with chloroform and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. To the resulting residue were added di-tert-butyl dicarbonate (372 mg), 1,4-dioxane (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml), and the resulting mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether, followed by filtration, and the precipitate was washed with hexane to obtain the title compound (200 mg) as a light-yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.07 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 5.44 (s, 1H), 3.71-3.53 (m, 2H), 3.47-3.35 (m, 1H), 3.31 (s, 3H), 3.19 (s, 3H), 2.76-2.65 (m, 1H), 2.62-2.53 (m, 1H), 1.85-1.65 (m, 2H), 1.57-1.28 (m, 2H), 1.44 (s, 9H).

MS (ESI+) 378 (M⁺+1, 100%).

Reference Example 11 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

A solution of tert-butyl [(3R)-1-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)piperidin-3-yl]carbamate (60 mg), 2-chlorobenzyl bromide (32 μl) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure and purified by a preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (10 mg) as a white amorphous substance.

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.36 (m, 1H), 7.18-7.07 (m, 2H), 6.51-6.42 (m, 1H), 5.67 (d, J=16.8 Hz, 1H), 5.59 (s, 1H), 5.56 (d, J=16.8 Hz, 1H), 3.85-3.74 (m, 1H), 3.48 (s, 3H), 3.36 (s, 3H), 3.12-3.03 (m, 1H), 2.82-2.62 (m, 3H), 1.80-1.47 (m, 4H), 1.43 (s, 9H).

MS (ESI+) 502 (M⁺+1, 100%).

Reference Example 12 tert-Butyl {1-[5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 13.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.30 (m, 1H), 6.92-6.83 (m, 1H), 6.22-6.13 (m, 1H), 5.62 (d, J=17.0 Hz, 1H), 5.61 (s, 1H), 5.52 (d, J=17.0 Hz, 1H), 3.85-3.72 (m, 1H), 3.48 (s, 3H), 3.35 (s, 3H), 3.14-3.03 (m, 1H), 2.83-2.64 (m, 3H), 1.79-1.45 (m, 4H), 1.42 (s, 9H).

MS (ESI+) 520 (M⁺+1, 100%).

Reference Example 13 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate

A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate (110 mg), 3-ethoxyphenol (31 μl) and potassium carbonate (39 mg) in N,N-dimethylformamide (2 ml) was stirred at 50° C. for 1 hour. After the reaction solution was allowed to cool, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (86 mg) as a white solid.

MS (ESI+) 633 (M⁺+1, 100%).

Reference Example 14 tert-Butyl (3R)-1-[2-[2-(aminocarbonyl)phenoxy]-5-(2-chlorobenzyl)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 1.

MS (ESI+) 632 (M⁺+1, 100%).

Reference Example 15 tert-Butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

To a mixed solution of dimethyl sulfoxide (250 ml) and water (25 ml) were added tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (17.9 g) and potassium carbonate (4.7 g). In a water bath, an aqueous hydrogen peroxide solution (a 30-35% aqueous solution, 17 ml) was added dropwise and the resulting mixture was stirred at 25° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed three times with water and then once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (15.6 g) as a light-yellow amorphous substance.

MS (ESI+) 545 (M⁺+1, 100%).

Reference Example 16 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-7-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Sodium azide (154 mg) and ammonium chloride (125 mg) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (250 mg) in N,N-dimethylformamide (4 ml), and the resulting mixture was stirred at 150° C. for 8 hours. Sodium azide (154 mg) and ammonium chloride (125 mg) were further added thereto and stirred for another 6 hours. After the reaction solution was cooled to 25° C., a 10% aqueous potassium hydrogensulfate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the title compound (23 mg) as a white solid.

MS (ESI+) 570 (M⁺+1, 100%).

Reference Example 17 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-7-(1H-pyrrolo-1-ylcarbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

After tert-butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (12.6 g) and 2,5-dimethoxytetrahydrofuran (150 ml) were stirred at 25° C., thionyl chloride (1.7 ml) was added dropwise thereto and the resulting mixture was stirred at 40° C. for 6 hours. After the reaction solution was cooled to 25° C., a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (15.9 g) as a yellow amorphous substance.

MS (ESI+) 595 (M⁺+1, 100%).

Reference Example 18 Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

Sodium methoxide (a 28% methanol solution, 0.2 ml) was added to a solution of tert-butyl [(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-7-(1H-pyrrolo-1-ylcarbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (410 mg) in methanol (5 ml), and the resulting mixture was stirred at 60° C. for 2 hours. After the reaction solution was cooled to 25° C., a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (380 mg) as a white amorphous substance.

MS (ESI+) 560 (M⁺+1, 100%).

Reference Example 19 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-7-(morpholin-4-ylcarbonyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

1-Hydroxybenzotriazole (117 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg), triethylamine (0.21 ml) and morpholine (63 μl) were added to a solution of 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (140 mg) in N,N-dimethylformamide (3 ml), and the resulting mixture was stirred at 25° C. for 20 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (106 mg) as a white solid.

MS (ESI+) 615 (M⁺+1, 100%).

Reference Example 20 6-{(3R)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid

A 1M aqueous sodium hydroxide solution (10 ml) was added to a solution of methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (2.08 g) in 1,4-dioxane (10 ml), and the resulting mixture was stirred at 80° C. for 5 hours. After the reaction solution was cooled to 25° C., a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (1.95 g) as a light-yellow amorphous substance.

MS (ESI+) 546 (M⁺+1, 100%).

Reference Example 21 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

In acetonitrile (5 ml) was dissolved 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (350 mg), and the solution was stirred at 80° C. for 1 hour. The reaction solution was cooled to 25° C. and concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (270 mg) as a white amorphous substance.

MS (ESI+) 402 (M⁺+1, 100%).

Reference Example 22 tert-Butyl {(3R)-1-[7-chloro-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (294 mg), and the resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 2 with a 10% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (917 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.41-7.38 (m, 1H), 7.20-7.10 (m, 2H), 6.42 (d, J=6.6 Hz, 1H), 5.78-5.70 (m, 2H), 3.79 (s, 3H), 3.59-3.55 (m, 1H), 3.36 (s, 3H), 3.12-2.80 (m, 4H), 1.64-1.43 (m, 4H), 1.42 (s, 9H).

MS (ESI+) 536 (M⁺+1, 100%).

Reference Example 23 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Paraformaldehyde (600 mg) and a 50% aqueous dimethylamine solution (1.80 g) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in a mixture of ethanol (10 ml) and acetic acid (5 ml), and the resulting mixture was stirred with heating at 80° C. After the reaction solution was cooled to 25° C., toluene (30 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was acidified with a 10% aqueous potassium hydrogensulfate solution and extracted twice with chloroform (100 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (913 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.37 (d, J=7.3 Hz, 1H), 7.18-7.07 (m, 2H), 6.31 (d, J=7.5 Hz, 1H), 5.71-5.58 (m, 2H), 3.84 (s, 3H), 3.46-3.12 (m, 4H), 3.36 (s, 3H), 2.89-2.64 (m, 3H), 2.22 (s, 6H), 1.79-1.45 (m, 4H), 1.42 (s, 9H).

MS (ESI+) 559 (M⁺+1, 43%).

Reference Example 24 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-(methoxymethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Methyl iodide (25 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (112 mg) in acetone (5 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in methanol (2 ml) was added 28% methanol methoxide (2 ml), followed by stirring with heating at 60° C. for 4 hours. The methanol was distilled off under reduced pressure and the residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a thin-layer silica gel column chromatography (hexane/ethyl acetate=1/5) to obtain the title compound (26 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.37 (d, J=7.7 Hz, 1H), 7.18-7.07 (m, 2H), 6.37 (d, J=7.0 Hz, 1H), 5.71-5.60 (m, 2H), 4.67-4.64 (m, 1H), 4.40 (s, 3H), 3.72 (s, 3H), 3.71-3.69 (m, 1H), 3.43 (s, 3H), 3.36 (s, 3H), 3.35-3.30 (m, 1H), 2.82-2.78 (m, 3H), 1.80-1.45 (m, 4H), 1.42 (s, 9H).

MS (ESI+) 546 (M⁺+1, 36%).

Reference Example 25 tert-Butyl {(3R)-1-[7-bromo-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in N,N-dimethylformamide (20 ml) was added N-bromosuccinimide (392 mg), and the resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 2 with a 10% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (1.143 g). ¹H NMR (300 MHz, CDCl₃) δ 7.39 (d, J=7.3 Hz, 1H), 7.20-7.10 (m, 2H), 6.40 (d, J=7.1 Hz, 1H), 5.76 (s, 2H), 4.97-4.95 (m, 1H), 3.83 (s, 3H), 3.67-3.59 (m, 1H), 3.36 (s, 3H), 3.23-2.82 (m, 3H), 2.54-2.52 (m, 1H), 1.91-1.89 (m, 1H), 1.71-1.51 (m, 3H), 1.43 (sm, 9H).

MS (ESI+) 582 (M⁺+1, 52%).

Reference Example 26 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-fluoro-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Xenon fluoride (56 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-ylcarbamate (1.00 g) in acetonitrile (10 ml), and the resulting mixture was stirred overnight at room temperature. After a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, the acetonitrile was distilled off under reduced pressure, and the residue was extracted twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a thin-layer silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (8 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.41-7.37 (m, 1H), 7.20-7.11 (m, 2H), 6.46 (d, J=6.8 Hz, 1H), 5.69 (d, J=16.3 Hz, 1H), 5.59 (d, J=16.3 Hz, 1H), 4.73-4.69 (m, 1H), 3.76-3.74 (m, 1H), 3.61 (s, 3H), 3.36 (s, 3H), 3.29-3.25 (m, 1H), 2.78-2.76 (m, 3H), 1.69-1.45 (m, 4H), 1.42 (s, 9H).

MS (ESI+) 520 (M⁺+1, 17%).

Reference Example 27 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3,7-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Methyl iodide (38 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (168 mg) in acetone (4 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in tetrahydrofuran (5 ml) was added a 1N aqueous sodium hydroxide solution (3 ml), followed by stirring with heating at 60° C. for 3 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. Then, a solution of the resulting residue in dichloromethane (6 ml) was added dropwise to an ice-cooled solution of triethylsilane (144 μl) and methanesulfonic acid (60 μl) in dichloromethane (10 ml), and the resulting mixture was stirred at 0° C. for 1 hour. A 10% aqueous potassium carbonate solution was added thereto, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (101 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.37 (d, J=7.3 Hz, 1H), 7.17-7.07 (m, 2H), 6.35 (d, J=6.7 Hz, 1H), 5.70 (s, 1H), 4.93-4.91 (m, 1H), 4.93-4.91 (m, 1H), 3.75-3.73 (m, 1H), 3.70 (s, 3H), 3.36 (s, 3H), 3.31-3.29 (m, 1H), 2.90-2.63 (m, 3H), 2.33 (s, 3H), 1.92-1.90 (m, 1H), 1.63-1.46 (m, 3H), 1.42 (s, 9H).

MS (ESI+) 516 (M⁺+1, 61%).

Reference Example 28 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Phosphorus oxychloride (551 μl) was added to dimethylformamide (10 ml) at room temperature and stirred for 5 minutes. A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (502 mg) in N,N-dimethylformamide (1 ml) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (290 mg).

¹H NMR (300 MHz, CDCl₃) δ 10.10 (s, 1H), 7.43-7.40 (m, 1H), 7.23-7.12 (m, 2H), 6.46 (d, J=7.1 Hz, 1H), 5.80 (d, J=16.0 Hz, 1H), 5.59 (d, J=16.0 Hz, 1H), 4.61-4.59 (m, 1H), 3.84 (s, 3H), 3.66-3.64 (m, 1H), 3.38 (s, 3H), 3.37-3.31 (m, 1H), 2.90-2.85 (m, 3H), 1.88-1.85 (m, 1H), 1.59-1.55 (m, 3H), 1.42 (s, 9H).

MS (ESI+) 530 (M⁺+1, 39%).

Reference Example 29 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-(1-hydroxyethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl carbamate

A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (132 mg) in tetrahydrofuran (4 ml) was cooled to 0° C., followed by adding thereto methylmagnesium bromide (417 μl), and the resulting mixture was stirred at 0° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (167 mg).

MS (ESI+) 546 (M⁺+1, 46%).

Reference Example 30 tert-Butyl {(3R)-1-[7-acetyl-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Manganese dioxide (0.66 g) was added to a solution of crude tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-(1-hydroxyethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (167 mg) in dichloromethane (5 ml), and the resulting mixture was stirred overnight at room temperature. Then, the reaction solution was heated to 45° C. and stirred for 3 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (33 mg).

MS (ESI+) 546 (M⁺+1, 46%).

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.38 (m, 1H), 7.22-7.11 (m, 2H), 6.43-6.40 (m, 1H), 5.77-5.60 (m, 2H), 5.54-5.51 (m, 1H), 3.62-3.60 (m, 1H), 3.42 (s, 3H), 3.36 (s, 3H), 3.34-3.32 (m, 1H), 2.79-2.65 (m, 3H), 2.59 (s, 3H), 1.88-1.82 (m, 1H), 1.65-1.48 (m, 2H), 1.42 (s, 9H).

MS (ESI+) 544 (M⁺+1, 34%).

Reference Example 31 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Bis(dibenzylideneacetone)palladium (18 mg), tri-tert-butylphosphonium tetrafluoroborate (22 mg), potassium phosphate (329 mg) and 4-methoxyphenylboronic acid (236 mg) were added to a solution of tert-butyl [(3R)-1-[7-bromo-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (90 mg) in dioxane (4 ml), and the resulting mixture was stirred with heating at 50° C. for 15 hours. The reaction solution was filtered through Celite and washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. A 10% aqueous potassium carbonate solution was added to the residue, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (10 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.41-7.37 (m, 1H), 7.26-7.10 (m, 4H), 6.92 (d, J=8.8 Hz, 1H), 6.52-6.50 (m, 1H), 5.80 (d, J=16.7 Hz, 1H), 5.66 (d, J=16.7 Hz, 1H), 3.87 (s, 3H), 3.52-3.50 (m, 1H), 3.37 (s, 3H), 3.07 (s, 3H), 2.80-2.40 (m, 4H), 1.62-1.39 (m, 4H), 1.38 (s, 9H)

MS (ESI+) 608 (M⁺+1, 76%).

Reference Example 32 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

4-Methoxybenzyl isocyanate (0.5 ml) and potassium carbonate (486 mg) were added to a solution of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (920 mg) in pyridine (1 ml), and the resulting mixture was stirred at 130° C. for 6 hours. 4-Methoxybenzyl isocyanate (2.0 ml) was added thereto, followed by stirring with heating for another 24 hours. The reaction solution was cooled to 25° C. and then concentrated under reduced pressure and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (15 ml), followed by adding thereto potassium carbonate (486 mg) and methyl iodide (0.33 ml), and the resulting mixture was stirred at 25° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (750 mg) as a light-yellow amorphous substance.

MS (ESI+) 651 (M⁺+1, 100%).

Reference Example 33 tert-Butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-chloro-5-fluorobenzyl)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 15.

MS (ESI+) 669 (M⁺+1, 100%).

Reference Example 34 Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

The title compound was synthesized from a corresponding compound by the same process as in Reference Examples 17 and 18.

MS (ESI+) 684 (M⁺+1, 100%).

Reference Example 35 Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

Under a nitrogen atmosphere, a solution of aluminum chloride (395 mg) in anisole (1.5 ml) was added to methyl 6-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (260 mg), and the resulting mixture was stirred at 65° C. for 4 hours. After the reaction solution was cooled to 25° C., 1N hydrochloric acid was added thereto and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized with a 1N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the resulting residue were added di-tert-butyl dicarbonate (415 mg), 1,4-dioxane (4 ml) and a saturated aqueous sodium hydrogencarbonate solution (4 ml) and the resulting mixture was stirred at 25° C. for 16 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether/hexane and the resulting mixture was filtered and then washed with hexane to obtain the title compound (121 mg) as a light-yellow solid.

MS (ESI+) 564 (M⁺+1, 100%).

Reference Example 36 Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-3-(2-oxo-2-phenylethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

A solution of methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (50 mg), α-bromoacetophenone (27 mg) and potassium carbonate (25 mg) in N,N-dimethylformamide was stirred at 25° C. for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (51 mg) as a white solid.

MS (ESI+) 682 (M⁺+1, 100%).

Reference Example 37 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-3-(2-oxo-2-phenylethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Examples 20 and 21.

MS (ESI+) 624 (M⁺+1, 100%).

Reference Example 38 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Methyl isothiocyanate (7.36 ml) and potassium carbonate (14.86 g) were added to a solution (200 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (27.96 g) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 13 hours. After the reaction solution was cooled to 25° C., toluene (50 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and the solid precipitated was collected by filtration and washed with water and then hexane. The solid thus obtained was dried at 45° C. under reduced pressure to obtain the title compound (28.56 g).

MS (ESI+) 547 (M⁺+1, 86%).

Reference Example 39 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Sodium tungstate dihydrate (0.91 g) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.51 g) in a mixture of methanol (9 ml), acetic acid (3 ml) and water (1 ml), and a 30% aqueous hydrogen peroxide solution (0.29 ml) was added dropwise thereto at room temperature and stirred for 2 hours. After the reaction mixture was allowed to cool, the methanol was distilled off under reduced pressure and the residue was adjusted to pH 9 with an aqueous potassium carbonate solution. A 10% aqueous sodium hydrogensulfite solution was added thereto and stirred for 30 minutes, followed by extraction with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was dried under reduced pressure to obtain the title compound (1.61 g).

¹H NMR (300 MHz, CDCl₃) δ 7.99 (s, 1H), 7.41-7.36 (m, 1H), 6.96-6.89 (m, 1H), 6.20 (d, J=7.5 Hz, 1H), 5.70 (d, J=16.7 Hz, 1H), 5.59 (d, J=16.7 Hz, 1H), 4.53-4.51 (m, 1H), 3.74-3.69 (m, 1H), 3.55 (s, 3H), 3.52-3.46 (m, 1H), 3.05-2.94 (m, 3H), 1.88-1.85 (m, 1H), 1.70-1.60 (m, 3H), 1.41 (s, 9H).

MS (ESI+) 515 (M⁺+1, 66%).

Reference Example 40 tert-Butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-chloro-5-fluorobenzyl)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 15.

MS (ESI+) 533 (M⁺+1, 73%).

Reference Example 41 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-3-methyl-4-oxo-7-(1H-pyrrolo-1-ylcarbonyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 17.

MS (ESI+) 583 (M⁺+1, 100%).

Reference Example 42 Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)-amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 18.

¹H NMR (300 MHz, CDCl₃) δ 8.04 (s, 1H), 7.40-7.35 (m, 1H), 6.93-6.86 (m, 1H), 6.03 (d, J=7.1 Hz, 1H), 5.85 (d, J=16.8 Hz, 1H), 5.74 (d, J=16.8 Hz, 1H), 4.68-4.66 (m, 1H), 3.98 (s, 3H), 3.68-3.66 (m, 1H), 3.56 (s, 3H), 3.33-3.31 (m, 1H), 2.97-2.93 (m, 3H), 1.83-1.81 (m, 1H), 1.65-1.56 (m, 3H), 1.41 (s, 9H).

MS (ESI+) 548 (M⁺+1, 41%).

Reference Example 43 6-{(3R)-3-[(tert-Butoxycarbonyl)amino]-piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 20.

MS (ESI+) 534 (M⁺+1, 6%).

Reference Example 44 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-3-methyl-7-(morpholin-4-ylcarbonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 19.

¹H NMR (300 MHz, CDCl₃) δ 7.89 (s, 1H), 7.39-7.34 (m, 1H), 6.92-6.87 (m, 1H), 6.21-6.19 (m, 1H), 5.74 (d, J=16.6 Hz, 1H), 5.59 (d, J=16.6 Hz, 1H), 4.60-4.58 (m, 1H), 3.92-3.71 (m, 7H), 3.57-3.51 (m, 2H), 3.54 (s, 3H), 3.30-3.28 (m, 1H), 2.87-2.76 (m, 3H), 1.78-1.57 (m, 4H), 1.41 (s, 9H).

MS (ESI+) 603 (M⁺+1, 19%).

Reference Example 45 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

The title compound was synthesized from a corresponding compound by the same process as in Reference Example 21.

¹H NMR (300 MHz, CDCl₃) δ 7.88 (s, 1H), 7.37-7.32 (m, 1H), 6.90-6.83 (m, 1H), 6.09 (d, J=9.3 Hz, 1H), 6.06 (s, 1H), 5.73 (d, J=16.9 Hz, 1H), 5.62 (d, J=16.9 Hz, 1H), 4.69-4.65 (m, 1H), 3.80-3.78 (m, 1H), 3.54 (s, 3H), 3.13-3.08 (m, 1H), 2.77-2.74 (m, 3H), 1.72-1.60 (m, 4H), 1.42 (s, 9H).

MS (ESI+) 490 (M⁺+1, 719%).

Reference Example 46 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Methanesulfonic acid (21 μl) and a 30% aqueous hydrogen peroxide solution (54 μl) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (132 mg) in methanol (4 ml), and the resulting mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium sulfite solution was added to the reaction solution, followed by extraction with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate 1/2) to obtain the title compound (54 mg).

¹H NMR (300 MHz, CDCl₃) δppm 7.35 (d, J=7.5 Hz, 1H), 7.17-7.07 (m, 2H), 6.37 (d, J=6.8 Hz, 1H), 5.86 (brs, 1H), 5.60-5.56 (m, 2H), 4.82 (brs, 1H), 3.71 (s, 3H), 3.65-3.63 (m, 1H), 3.37 (s, 3H), 3.35-3.33 (m, 1H), 2.84-2.70 (m, 3H), 1.95-1.93 (m, 1H), 1.62-1.41 (m, 3H), (m, 9H).

MS (ESI+) 518 (M⁺+1, 82%).

Reference Example 47 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-2,7-dicyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

An aqueous solution (2 ml) of sodium cyanide (338 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (758 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.37 (m, 1H), 6.99-6.91 (m, 1H), 6.19 (d, J=7.3 Hz, 1H), 5.68 (d, J=16.7 Hz, 1H), 5.57 (d, J=16.7 Hz, 1H), 4.52-4.49 (m, 1H), 3.78 (s, 3H), 3.72-3.70 (m, 1H), 3.55-3.50 (m, 1H), 3.10-3.06 (m, 2H), 3.00-2.93 (m, 1H), 1.91-1.89 (m, 1H), 1.74-1.58 (m, 3H), 1.41 (s, 9H).

MS (ESI+) 540 (M⁺+1, 11%).

Reference Example 48 tert-Butyl {(3R)-1-[2-(aminocarbonyl)-5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Potassium carbonate (42 mg) and then an aqueous hydrogen peroxide solution (a 30-35% aqueous solution, 170 μl) were added dropwise to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-2,7-dicyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (162 mg) in a mixture of dimethyl sulfoxide (10 ml) and water (2 ml), and the resulting mixture was stirred overnight at room temperature. A 10% aqueous sodium sulfite solution was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (77 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.62 (s, 1H), 7.42-7.37 (m, 1H), 6.97-6.91 (m, 1H), 6.21 (d, J=7.0 Hz, 1H), 5.84 (s, 1H), 5.71 (d, J=16.7 Hz, 1H), 5.60 (d, J=16.7 Hz, 1H), 4.58-4.55 (m, 1H), 3.87 (s, 3H), 3.75-3.73 (m, 1H), 3.54-3.49 (m, 1H), 3.05-2.95 (m, 3H), 1.87-1.85 (m, 1H), 1.70-1.66 (m, 3H), 1.42 (s, 9H).

MS (ESI+) 458 (M⁺+1, 100%).

Reference Example 49 tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-methoxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Potassium carbonate (41 mg) and methyl iodide (13 μl) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (50 mg) in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at room temperature for 5 hours. A 10% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (17 mg).

MS (ESI+) 532 (M⁺+1, 69%).

Reference Example 50 tert-Butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

A solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (2 ml) was cooled to 0° C. and a 3M methylmagnesium bromide/diethyl ether solution (333 μl) was added dropwise thereto. After 30 minutes, the reaction solution was warmed to room temperature and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (64 mg).

¹H NMR (300 MHz, CDCl₃₃) δ 7.40-7.35 (m, 1H), 6.95-6.88 (m, 1H), 6.18 (d, J=6.9 Hz, 1H), 5.68 (d, J=16.8 Hz, 1H), 5.57 (d, J=16.8 Hz, 1H), 4.58-4.55 (m, 1H), 3.78-3.74 (m, 1H), 3.54 (s, 3H), 3.50-3.45 (m, 1H), 3.04-2.94 (m, 3H), 2.63 (s, 3H), 1.88-1.83 (m, 1H), 1.68-1.62 (m, 2H), 1.43-1.41 (m, 1H), 1.41 (s, 9H).

MS (ESI+) 529 (M⁺+1, 100%).

In Vitro DPP-IV Inhibitory Effect Measurement Test

Human serum containing DPP-IV enzyme was diluted finally 9- to 20-fold with assay buffer and added to a microassay plate. Each of solutions of each test compound having various concentrations was added thereto, followed by adding thereto a substrate (Glycyl-L-Proline 4-Methyl-Coumaryl-7-Amide, Peptide Laboratories Co., Ltd.) to a final concentration of 10 to 100 μM, and the reaction was carried out at room temperature. Acetic acid was added thereto to a final concentration of 0.5% to terminate the reaction, and the intensity of fluorescence at an excitation wavelength of 360 nm and a measuring wavelength of 460 nm was measured by the use of a fluorescent plate reader. A compound concentration for 50% inhibition was calculated as an IC₅₀ value from enzyme inhibiting activity values obtained by adding each test compound to a plurality of concentrations.

TABLE 1 Human DPP IV Human DPPIV Test inhibiting Test inhibiting Compound activity IC₅₀ (nM) compound activity IC₅₀ (nM) Example 1 76 Example 34 5.8 Example 2 21 Example 37 10 Example 3 26 Example 38 5.3 Example 4 28 Example 39 4.1 Example 5 15 Example 40 6.8 Example 6 1.9 Example 41 4.1 Example 7 60 Example 42 5.7 Example 8 7.4 Example 43 6.9 Example 14 55 Example 44 9.0 Example 18 12 Example 45 4.8 Example 19 7.1 Example 46 5.6 Example 20 4.3 Example 56 31 Example 24 44 Example 60 28 Example 25 7.6 Example 61 85 Example 26 3.2 Example 62 56 Example 27 9.8 Example 63 27 Example 28 6.4 Example 64 13 Example 29 5.7 Example 65 6.2 Example 30 4.7 Example 66 5.5 Example 31 5.0 Example 70 3800 Example 32 7.5 Example 72 1200 Example 33 12.0

INDUSTRIAL APPLICABILITY

The present invention makes it possible to provide compounds that have DPP-IV inhibitory activity and possess improved safety, non-toxicity and the like.

The present inventive compounds are useful for the suppression of postprandial hyperglycemia in prediabetes, the treatment of non-insulin-dependent diabetes, the treatment of autoimmune diseases such as arthritis and articular rheumatism, the treatment of intestinal mucosa diseases, growth acceleration, the inhibition of transplantation rejection, the treatment of obesity, the treatment of eating disorder, the treatment of HIV infection, the suppression of cancer metastasis, the treatment of prostatomegaly, the treatment of periodontitis, and the treatment of osteoporosis. 

1. A compound represented by the formula (I):

wherein R¹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; the solid line and dotted line between A¹ and A² indicate a double bond (A¹=A²) or a single bond (A¹-A²); A¹ is a group represented by the formula C(R⁴) and A² is a nitrogen atom, in the case of the solid line and dotted line between A¹ and A² being a double bond (A¹=A²); Λ¹ is a group represented by the formula C═O and A² is a group represented by the formula N(R⁵), in the case of the solid line and dotted line between A¹ and A² being a single bond (A¹-A²); R² is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group; R³ is a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkoxy group, or the formula: -Rd-C(O)O—Re wherein Rd is a single bond, an alkylene group or an alkenylene group and Re is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-(tert-butyl)-2-oxo-1,3-dioxolen-4-ylmethyl or the formula: —CH(R^(4a))OC(O)R^(4b) wherein R^(4a) is a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group or an alkoxy group and R^(4b) is an optionally substituted alkyl group, an optionally substituted alkenyl group, a cycloalkyl group, a cycloalkyloxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, a 2-indanyloxy group, a 5-indanyloxy group or an optionally substituted aryloxy group; R⁴ is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined above; R⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted vinyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, or an optionally substituted heteroaryl group; —Y is a group represented by any of the formula (A), formula (B), formula (C) and formula (D) shown below:

wherein m1 is 0, 1, 2 or 3, and R⁶ is absent or one or two R⁶s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁶s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;

wherein m2 is 0, 1, 2 or 3, and R⁷ is absent or one or two R⁷s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁷s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;

wherein m3 and m4 are independently 0 or 1, and R⁸ is absent or one or two R⁸s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁸s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; and

wherein m5 is 1, 2 or 3, R⁹ is absent or one or two R⁹s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R⁹s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring, and R¹⁰ and R¹¹ are independently a hydrogen atom, methyl, ethyl, propyl or isopropyl, or R¹⁰ and R¹¹, when taken together, represent cyclopropyl, cyclobutyl or cyclopentyl, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug.
 2. A compound according to claim 1, which is represented by the formula (II):

wherein R¹, R², R³ and Y are as defined in claim 1 and R¹² is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
 3. A compound according to claim 1, which is represented by the formula (III):

wherein R¹, R², R³ and Y are as defined in claim 1 and R¹³ is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in claim 1, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
 4. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 3, wherein R¹³ is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, a trifluoromethyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aroyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in claim
 1. 5. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1, wherein R² is a group represented by any of the following formula (E), formula (F), formula (G), formula (H), formula (I) and formula (J):

wherein each of Z¹ and Z² is an oxygen atom, the formula S(O)_(p) or the formula N(R²²); each of R¹⁴ and R²⁰ is absent or one or two R¹⁴s and/or one or two R²⁰s are present and are independently a halogen atom, a hydroxyl group, a formyl group, a carboxyl group, a cyano group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a cycloalkylcarbonyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing heteroaryl group, or two R¹⁴s or two R²⁰s, when taken together, represent a C₁₋₃ alkylenedioxy group; each of R¹⁵ and R²¹ is absent or one or two R¹⁵s and/or one or two R²¹s are present and are independently a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group or a haloalkoxy group; R¹⁶ is methyl, ethyl, a chlorine atom or a bromine atom; R¹⁷ is a hydrogen atom, methyl, ethyl, a chlorine atom or a bromine atom; R¹⁸ is a hydrogen atom, methyl or ethyl; R¹⁹ is a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl; p is 0, 1 or 2; and R²² is a hydrogen atom or an alkyl group.
 6. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1, wherein —Y is a group represented by the formula (A) in which m1 is 1 or 2, or —Y is a group represented by the formula (B) in which m2 is 1 or 2, or —Y is a group represented by the formula (C) in which each of m3 and m4 is
 1. 7. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1, wherein R² is a group represented by any of the formula (E), formula (H) and formula (I).
 8. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1, wherein R¹ is a hydrogen atom, an optionally substituted C₁-C₃ alkyl group or an optionally substituted aryl group, and the substituent(s) of the optionally substituted alkyl group is selected from fluorine atom, optionally substituted aroyl groups, carboxyl group, optionally substituted alkoxycarbonyl groups, optionally substituted aryl groups and optionally substituted aryloxy groups.
 9. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1, wherein R¹ is a group represented by the formula: —Ra—Rb-Rc in which Ra is an alkylene group; Rb is a single bond or a carbonyl group; and Rc is an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group or an optionally substituted heteroarylamino group.
 10. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1, wherein R¹ is a hydrogen atom, methyl or ethyl.
 11. A compound according to claim 1, which is represented by the formula (IV):

wherein R¹ and R³ are as defined in claim 1; R²³ is a hydrogen atom or an optionally substituted alkyl group; R²⁴ is a halogen atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group; and R²⁵ is a hydrogen atom, a fluorine atom or a chlorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
 12. A compound according to claim 1, which is represented by the formula (V):

wherein R²⁶ is a hydrogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted carbamoyl group, a hydroxyl group or an optionally substituted alkoxy group; R²⁷ is a chlorine atom, a bromine atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group; and R²⁸ is a hydrogen atom or a fluorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
 13. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 12, wherein R²⁷ is a chlorine atom or a cyano group.
 14. A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 12, wherein R²⁶ is a hydrogen atom or an optionally substituted carbamoyl group.
 15. A compound represented by the formula (VI):

wherein R² and Y are as defined in claim 1 and R²⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
 16. A pharmaceutical composition comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1 as an active ingredient.
 17. A dipeptidyl peptidase IV inhibitor comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1 as an active ingredient.
 18. A pharmaceutical composition for the treatment of diabetes comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1 as an active ingredient.
 19. Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1 in the manufacture of a dipeptidyl peptidase IV inhibitor.
 20. Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1 in the manufacture of a pharmaceutical composition for the treatment of diabetes.
 21. A method for treating diabetes comprising administering an effective amount of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to claim 1 to a patient who needs the treatment. 